Benzimidazole derivatives

ABSTRACT

Novel benzimidazole derivatives represented by the formula (I): ##STR1## wherein R 3  is a carboxyl group, a esterified carboxyl group, an amidated carboxyl group, an amino group, an amido group, or a sulfonyl group, or their pharmaceutically acceptable salts. Because of their blood sugar-depressing effect or PDE5 inhibitory effect, these compounds or salts thereof are useful as medicines for treating impaired glucose tolerance, diabetes, diabetic complications, syndrome of insulin resistance, hyperlipidemia, atherosclerosis, cardiovascular disorders, hyperglycemia, or hypertension; or stenocardia, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy, tubulointerstitial disorders, renal failure, atherosclerosis, angiostenosis, distal angiopathy, cerebral apoplexy, chronic reversible obstructions, allergic rhinitis, urticaria, glaucoma, diseases characterized by enteromotility disorders, impotence, diabetic complications, nephritis, cancerous cachexia, or restenosis after PTCA.

TECHNICAL FIELD

The present invention relates to novel benzimidazole derivatives, and,more precisely, to novel benzimidazole derivatives and theirpharmaceutically acceptable salts having blood sugar level-depressingactivity or PDE5-inhibiting activity. The present invention also relatesto pharmaceutical compositions comprising, as an active ingredient, suchbenzimidazole derivatives or their salts.

DISCLOSURE OF THE INVENTION

The subject matter of the present invention is to provide novelbenzimidazole derivatives and their pharmaceutically acceptable salts,and also pharmaceutical compositions which comprise, as an activeingredient, such benzimidazole derivatives or their pharmaceuticallyacceptable salts, and which are useful for preventing and treatingimpaired glucose tolerance, diabetes (type II diabetes), diabeticcomplications (e.g., diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, etc.), syndrome of insulin resistance (e.g., insulinreceptor disorders, Rabson-Mendenhall syndrome, leprechaunism,Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushingsyndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis,cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.),hyperglycemia (e.g., abnormal saccharometabolism such as feedingdisorders, etc.), or hypertension; or stenocardia, hypertension,pulmonary hypertension, congestive heart failure, glomerulopathy (e.g.,diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g.,renopathy induced by FK506, cyclosporin, etc.), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),distal angiopathy, cerebral apoplexy, chronic reversible obstructions(e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.),allergic rhinitis, urticaria, glaucoma, diseases characterized byenteromotility disorders (e.g., hypersensitive enteropathy syndrome,etc.), impotence (e.g., organic impotence, psychic impotence, etc.), anddiabetic complications (e.g., diabetic gangrene, diabetic arthropathy,diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerouscachexia, or restenosis after PTCA.

The present inventors provide pharmaceutical compositions comprising, asan active ingredient, any of benzimidazole derivatives of the followingformulae (I) to (IV) and (VIII) to (XIV), and their pharmaceuticallyacceptable salts, which is usable for preventing and treating impairedglucose tolerance, diabetes (type II diabetes), diabetic complicationssuch as diabetic nephropathy, diabetic neuropathy and diabeticretinopathy, syndrome of insulin resistance (e.g., insulin receptordisorders, Rabson-Mendenhall syndrome, leprechaunism,Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushingsyndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis,cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.),hyperglycemia (e.g., abnormal saccharometabolism such as feedingdisorders, etc.), or hypertension; or stenocardia, hypertension,pulmonary hypertension, congestive heart failure, glomerulopathy (e.g.,diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g.,renopathy induced by FK506, cyclosporin, etc.), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),distal angiopathy, cerebral apoplexy, chronic reversible obstructions(e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.),allergic rhinitis, urticaria, glaucoma, diseases characterized byenteromotility disorders (e.g., hypersensitive enteropathy syndrome,etc.), impotence (e.g., organic impotence, psychic impotence, etc.), anddiabetic complications (e.g., diabetic gangrene, diabetic arthropathy,diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerouscachexia, or restenosis after PTCA. ##STR2## In formula (I); R₁represents a hydrogen atom, an arylsulfonyl group, or a lower alkylgroup; said lower alkyl group may be substituted by an aryl group or anaryl group substituted by one or two substituents selected from ahalogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a nitro group, an amino group, a cyanogroup, an aryl group, an aryl-lower alkyl group, an aryl-lower alkyloxygroup, a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkylgroup, an arylsulfonylamino group, a cyanoaryl group, and a heterocyclicgroup, or by a heterocyclic group;

R₂ represents a hydrogen atom, a lower cycloalkyl group, a hydroxylgroup, a lower alkoxy group, a mercapto group, a lower alkylthio group,an amino group, a lower alkylamino group, a carboxyl group, an arylgroup, or a lower alkyl group; said lower alkyl group may be substitutedby a halogen atom, a lower alkoxy group, a cyano group, a chlorocarbonylgroup, an aryl group, or a heterocyclic group;

R₃ represents a carboxyl group, an esterified carboxyl group, anamidated carboxyl group, an amino group, an amido group, or a sulfonylgroup; said amino group and said amido group may be substituted by anacyl group or a sulfonyl group; and a halogen atom, an amino group, oran acylamino group is bonded to said sulfonyl group; or R₃ may be bondedto the skeleton via a lower alkylene or alkenylene group;

R₄ represents a neutral substituent; and

n means an integer from 0 to 3. ##STR3## In formula (II); R₆ representsan aryl-lower alkyl group or an aryl-lower alkyl group substituted byone or two substituents selected from a halogen atom, a haloaryl group,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, anitro group, an amino group, a cyano group, an aryl group, a cyanoarylgroup, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group,an arylsulfonylamino group, an aryl-lower alkyl group, and aheterocyclic group;

R₇ represents a lower alkyl group or a lower cycloalkyl group;

R₈ represents a carbamoyl group, which may be substituted by a loweralkyl group, a lower alkyl group substituted by a substituted orunsubstituted aryl group or a substituted or unsubstituted heterocyclicgroup, an aryl group, a heterocyclic group, or a group of: ##STR4## inwhich R₉ represents an alkyl group having up to 8 carbon atoms, ahalo-lower alkyl group, an aryl-lower alkyl group, a hydroxy-lower alkylgroup, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-loweralkyl group, a lower alkylthio-lower alkyl group, a heterocyclic group,or an aryl group; said aryl group may be substituted by a halogen atom,a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, ora nitro group;

or R₈ may be bonded to the skeleton via a lower alkylene or alkenylenegroup;

R₄ ' represents a hydrocarbon group or a halogenated hydrocarbon group;and

n means an integer from 0 to 3. ##STR5## In formula (III); R₆ representsan aryl-lower alkyl group or an aryl-lower alkyl group substituted byone or two substituents selected from a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a nitro group, anamino group, a cyano group, an aryl group, a haloaryl group, a cyanoarylgroup, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group,an arylsulfonylamino group, an aryl-lower alkyl group, and aheterocyclic group;

R₇ represents a lower alkyl group or a lower cycloalkyl group;

R₁₁ represents a substitutent of a formula: ##STR6## in which R₁₂represents an alkyl group having up to 8 carbon atoms, a halo-loweralkyl group, an aryl-lower alkyl group, a hydroxy-lower alkyl group, atri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkylgroup, a lower alkylthio-lower alkyl group, a heterocyclic group, or anaryl group; said aryl group may be substituted by a halogen atom, alower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or anitro group;

or R₁₁ may be bonded to the skeleton via a lower alkylene or alkenylenegroup;

R₄ ' represents a hydrocarbon group or a halogenated hydrocarbon group;and

n means an integer from 0 to 3. ##STR7## In formula (IV); R₁₃ representsan aryl-lower alkyl group or an aryl-lower alkyl group substituted byone or two substituents selected from a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkoxy group, a nitro group, anamino group, a cyano group, an aryl group, a haloaryl group, a cyanoarylgroup, an aryl-lower alkyl group, an arylsulfonyl-lower alkyl group, anarylsulfonylamino group, and a heterocyclic group;

R₁₄ represents a lower alkyl group;

R₁₅ represents a substitutent of a formula: ##STR8## in which R₁₆represents a lower alkyl group or an aryl group; R₄ ' represents ahydrocarbon group or a halogenated hydrocarbon group; and

n means an integer from 0 to 3. ##STR9## In formula (VIII); R₁represents a hydrogen atom, an arylsulfonyl group, or a lower alkylgroup; said lower alkyl group may be substituted by an aryl group or anaryl group substituted by one or two substituents selected from ahalogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a nitro group, an amino group, a cyanogroup, an aryl group, an aryl-lower alkyloxy group, anarylsulfonyl-lower alkyl group, an aryl-lower alkyl group, ahaloaryl-lower alkyloxy group, an arylsulfonylamino group, anarylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, acyanoaryl group, and a heterocyclic group, or by a heterocyclic group;

R₂ represents a hydrogen atom, a lower cycloalkyl group, a hydroxylgroup, a hydroxy-lower alkyl group, a lower alkoxy group, a mercaptogroup, a lower alkylthio group, an amino group, a lower alkylaminogroup, a carboxyl group, an aryl group, or a lower alkyl group; saidlower alkyl group may be substituted by a halogen atom, a lower alkoxygroup, a cyano group, a halocarbonyl group, an aryl group, or aheterocyclic group;

R₂₅ represents an alkyl group having up to 8 carbon atoms, a lowercycloalkyl group, a halo-lower alkyl group, a tri-lower alkylsilyl-loweralkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-loweralkyl group, an aryl group, a heterocyclic group, an aryl-lower alkylgroup, or a hydroxy-lower alkyl group; said aryl group may besubstituted by a halogen atom, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, or a nitro group;

R₂₆ represents a hydrogen atom or a lower alkyl group; provided that,when R₂₅ and R₂₆ are both lower alkyl groups, they may be bondedtogether to form a ring;

Y represents a carbonyl group or a lower alkylene group;

A represents a single bond, or a lower alkylene or alkenylene group;

R₄ ' represents a hydrocarbon group or a halogenated hydrocarbon group;and

n means an integer from 0 to 3. ##STR10## In formula (IX); R₂₇represents a hydrogen atom, an alkyl group having up to 7 carbon atoms,a halo-lower alkyl group, an arylsulfonyl group, an aryl-lower alkylgroup, a heterocyclic lower alkyl group, or a halo-heterocyclic loweralkyl group; and the aromatic ring moiety in said aryl-lower alkyl groupmay be substituted by one or two substituents selected from a halogenatom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group,an amino group, a lower alkoxy group, a nitro group, a cyano group, anaryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, anarylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-loweralkyl group, a heterocyclic group, an aryloxy group, an arylcarbonylgroup, an arylcarbonylamino group, and an aryl-lower alkyloxy groupsubstituted by one or two halogen atoms;

R₂₈ represents a hydrogen atom, an alkyl group having up to 7 carbonatoms, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, alower cycloalkyl group, an aryl group, an aryl-lower alkyl group, alower alkylamino group, a lower alkoxy group, a lower alkylthio group, ahydroxyl group, a mercapto group, an amino group, or a carboxyl group;

R₂₅ represents an alkyl group having up to 8 carbon atoms, a halo-loweralkyl group, a tri-lower alkylsilyl-lower alkyl group, a loweralkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an arylgroup, a heterocyclic group, an aryl-lower alkyl group, or ahydroxy-lower alkyl group; and said aryl group may be substituted by ahalogen atom, a lower alkyl group, a halo-lower alkyl group, a loweralkoxy group, or a nitro group;

R₂₆ represents a hydrogen atom or a lower alkyl group; provided that,when R₂₅ and R₂₆ are both lower alkyl groups, they may be bondedtogether to form a ring;

Y represents a carbonyl group or a lower alkylene group;

A represents a single bond, or a lower alkylene or alkenylene group; and

R₂₉ represents a hydrogen atom or a lower alkyl group. ##STR11## Informula (X); R₃₀ represents a hydrogen atom, a lower alkyl group, asubstituted or unsubstituted aryl-lower alkyl group of a formula:##STR12## in which R₃₁ represents a hydrogen atom, a cyanoaryl group, anamino group, a lower alkoxy group, a nitro group, a cyano group, an arylgroup, a haloaryl group, an arylsulfonyl-lower alkyl group, anarylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-loweralkyl group, a heterocyclic group, or an aryloxy group,

or represents an aryl-lower alkyloxy group or an aryl-lower alkyloxygroup substituted by one or two halogen atoms, an arylsulfonyl group, aheterocyclic lower alkyl group, an arylcarbonylamino group, anarylcarbonyl group, an arylalkenyl group, or a lower alkylenedioxyarylgroup; and the alkyl moiety in said aryl-lower alkyl group may besubstituted by a lower alkyl group;

R₃₂ represents a hydrogen atom, a lower alkyl group, a halo-lower alkylgroup, a lower cycloalkyl group, an aryl group, an aryl-lower alkylgroup, a lower alkylamino group, a lower alkoxy group, a lower alkylthiogroup, a lower alkoxy-lower alkyl group, or a heterocyclic lower alkylgroup;

R₃₃ represents a carboxyl group, a lower alkoxycarbonyl group, a(2-cyanoaryl)oxycarbonyl group, or a group of a formula: ##STR13## inwhich Y represents a carbonyl group or a lower alkylene group; R₃₄represents a lower alkyl group or a lower alkyl group substituted by asubstituted or unsubstituted aryl or heterocyclic group, or representsan aryl group or a heterocyclic group;

A represents a single bond, or a lower alkylene or alkenylene group;

R₄ ' represents a hydrocarbon group or a halogenated hydrocarbon group.R₄ ' may include an alkyl group, an aralkyl group, an alkynyl group, andhalogenated groups of these. R₄ ' may be either saturated orunsaturated, may be either linear or cyclic, and may even be branched,as the case may be. For the halogenated groups, the type of the halogentherein is not specifically defined, and the number of the halogensubstituents therein is not also specifically defined. n means aninteger from 0 to 3. Therefore, one, two or three R₄ 's may be bonded tothe skeleton, or no R₄ ' may be bonded thereto. The position of R₄ ' isnot specifically defined and may be any of the ortho-position, themeta-position and the para-position relative to the other substituent.However, when R₃₀ is a hydrogen atom, n is 0, or that is, no R₄ ' isbonded to the skeleton. ##STR14## In formula (XI); R₃₅ represents ahydrogen atom, an aryl group, a lower alkoxy-lower alkyl group, a loweralkyl group, or an aryl-lower alkyl group;

R₃₆ represents a carboxyl group, a lower alkoxycarbonyl group, aheterocyclic lower alkylamino group, or a heterocyclic loweralkylcarbamoyl group;

R₃₇ and R₃₈ each independently represent a hydrogen atom, a halogenatom, a lower alkyl group, a halo-lower alkyl group, an aryl group, anaryl-lower alkyl group, or an aryl-lower alkyloxy group; and

A represents a single bond, or a lower alkylene or alkenylene group;provided that, when R₃₅ is a lower alkyl group, A is a lower alkylenegroup or a lower alkenylene group. ##STR15## In formula (XII); R₃₇ andR₃₈ each independently represent a hydrogen atom, a halogen atom, alower alkyl group, a halo-lower alkyl group, an aryl group, anaryl-lower alkyl group, or an aryl-lower alkyloxy group;

R₃₉ represents a lower alkyl group; and

R₄₀ represents a hydrogen atom, a lower alkoxycarbonyl group, a loweralkanoyl group, a lower alkanesulfonyl group, or a carbamoyl group.##STR16## In formula (XIII); R₃₇ and R₃₈ each independently represent ahydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkylgroup, an aryl group, an aryl-lower alkyl group, or an aryl-loweralkyloxy group; and

R₇ represents a lower alkyl group or a lower cycloalkyl group. ##STR17##In formula (XIV); R₃₇ and R₃₈ each independently represent a hydrogenatom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, anaryl group, an aryl-lower alkyl group, or an aryl-lower alkyloxy group;

R₇ represents a lower alkyl group or a lower cycloalkyl group;

R₄₁ represents a 2-pyridylcarbamoyl group, a2-carboxy-1-pyrrolidinocarbonyl group, anN-methyl-N-(2-pyridylmethyl)carbamoyl group, a homopiperidinocarbonylgroup, a [2-(N-oxo)-pyridylmethyl]carbamoyl group, a4-(dimethylamino)benzylcarbamoyl group, a piperonylcarbamoyl group, anN-methyl-N-(2-pyridyl)carbamoyl group, a thiomorpholinocarbonyl group, ahalosulfonyl group, an aminosulfonyl group, an acylaminosulfonyl group,a lower alkoxycarbonyl group, or a carboxyl group;

R₂₉ represents a hydrogen atom, or a lower alkyl group; provided that,when R₄₁ is a lower alkylcarbonyl group or a carboxyl group, R₂₉ is alower alkyl group.

The present invention also provides novel benzimidazole derivatives ofthe above-mentioned (VIII) to (XIV) and their salts.

Benzimidazole derivatives to be provided by the present invention can beproduced according to the following reaction formulae (a) to (f):##STR18##

In the above-mentioned reaction formulae, R_(1a) to R_(1f) may beselected from the above-mentioned R₁, R₆, R₁₃, R₁₇, R₂₂, R₂₃, R₂₇, R₃₀,or a substituted benzyl group of a formula: ##STR19## wherein R₃₇ andR₃₈ have the same meanings as those mentioned above. R_(2a) to R_(2f)may be selected from the above-mentioned R₂, R₇, R₁₄, R₁₈, R₂₈, R₃₂, R₃₅or R₃₉. The substituents R_(3a) to R_(3f) may be selected from asubstituent of a formula: ##STR20## with R₂₅, R₂₆, Y and A having thesame meanings as those mentioned above, or from the above-mentioned R₃,R₈, R₁₁, R₁₅, R₁₉, R₂₄, AR₃₃, AR₃₆, NHR₄₀, CN or R₄₁. The substituentsthat define R_(3a) through R_(3f) can be mutually converted to eachother. For example, as in the step (g) or (h) mentioned below, the ester(26) can be converted into the corresponding acid (27) or acid halide(28). The desired benzimidazoles can be produced through the reaction ofthese compounds with amines or sulfonamides. It is further possible togive various derivatives, as in the step (i) or (j) or (k) or (l) or (m)or (n) mentioned below. Such conversion of the groups, R_(3a) throughR_(3f) can be effected at any stage in the steps (a) through (f), whiledepending on the stability of R_(1a) to R_(1f) as well as R_(2a) toR_(2f) in the compounds and even on the easiness in the isolation of theproducts formed. ##STR21##

In this reaction formula, R₉ represents a lower alkyl group; andR_(1a-f) and R_(2a-f) have the same meanings as those mentioned above.##STR22##

In this reaction formula, Z' represents a chlorine atom or a bromineatom; and R_(1a-f) and R_(2a-f) have the same meanings as thosementioned above. ##STR23##

In this reaction formula, R_(1a-f) and R_(2a-f) have the same meaningsas those mentioned above. ##STR24##

In this reaction formula, R_(1a-f) and R_(2a-f) have the same meaningsas those mentioned above.

In the reaction step (a), a compound of formula (1) may be reacted witha base, such as sodium hydride, lithium diisopropylamide, lithiumhydrogencarbonate, lithium carbonate, lithium hydroxide, sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide, potassiumhydrogencarbonate, potassium carbonate, potassium hydroxide or the like,and with a compound to be represented by R_(1a) Z (where Z represents achlorine atom, a bromine atom, a toluenesulfonyloxy group, or amethanesulfonyloxy group) to give a compound of formula (2). Thecompound of formula (2) may be 1) reduced with reduced iron or zincunder an acidic condition, or 2) reduced with a transition metalcatalyst, such as typically palladium, platinum, ruthenium or nickel, ina hydrogen atmosphere, or 3) reduced with a transition metal catalyst,such as typically palladium, platinum, ruthenium or nickel, in thepresence of formic acid, or 4) reduced with sodium hydrosulfite, to beconverted into a compound of formula (3). In the process 1), thecompound of formula (3) is often cyclized in the reaction systemdirectly into a compound of formula (4). Depending on the compound offormula (2) being reduced, the compound of formula (4) may be partlyformed in any of the processes 1) to 4). The compound of formula (3) maybe processed with a carboxylic acid, a sulfonic acid or an inorganicacid, such as acetic acid, p-toluenesulfonic acid, hydrochloric acid,sulfuric acid, phosphoric acid or the like, to give the compound offormula (4).

In the step (b), a compound of formula (5) is may be hydrolyzed orsolvolyzed with a base, such as lithium hydrogencarbonate, lithiumcarbonate, lithium hydroxide, sodium hydrogencarbonate, sodiumcarbonate, sodium hydroxide, potassium hydrogencarbonate, potassiumcarbonate, potassium hydroxide or the like, or with a carboxylic acid, asulfonic acid or inorganic acid, such as acetic acid, p-toluenesulfonicacid, hydrochloric acid, sulfuric acid, phosphoric acid or the like,into a compound of formula (6). The compound of formula (6) may bereacted with a base, such as sodium hydride, lithium diisopropylamide,lithium hydrogencarbonate, lithium carbonate, lithium hydroxide, sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide, potassiumhydrogencarbonate, potassium carbonate, potassium hydroxide or the like,and with a compound to be represented by R_(1b) Z (where Z represents achlorine atom, a bromine atom, a toluenesulfonyloxy group, or amethanesulfonyloxy group) to give a compound of formula (7). Thecompound of formula (7) may be 1) reduced with reduced iron or zincunder an acidic condition, or 2) reduced with a transition metalcatalyst, such as typically palladium, platinum, ruthenium or nickel, ina hydrogen atmosphere, or 3) reduced with a transition metal catalyst,such as typically palladium, platinum, ruthenium or nickel, in thepresence of formic acid, or 4) reduced with sodium hydrosulfite, to beconverted into a compound of formula (8). A compound of formula (9) canbe produced from the compound of formula (8) and the correspondingcarboxylic acid or acid chloride or acid bromide or acid anhydride.

In the step (c), a compound of formula (11) can be produced from acompound of formula (10) and a compound to be represented by R_(1c) NH₂.The conversion of the compound of formula (11) to a compound of formula(13) is the same as that of the compound of formula (7) to the compoundof formula (9) in the step (b).

In the step (d), a compound of formula (14) may be 1) reduced with atransition metal catalyst such as typically palladium, platinum,ruthenium or nickel in a hydrogen atmosphere, or 2) reduced with sodiumhydrosulfite to give a compound of formula (15). The compound of formula(15) may be reacted with a base, such as lithium hydrogencarbonate,lithium carbonate, lithium hydroxide, sodium hydrogencarbonate, sodiumcarbonate, sodium hydroxide, potassium hydrogencarbonate, potassiumcarbonate, potassium hydroxide or the like, and with a compound to berepresented by R_(1d) Z (where Z represents a chlorine atom, a bromineatom, a toluenesulfonyloxy group, or a methanesulfonyloxy group) to givea compound of formula (16). The compound of formula (16) may be treatedwith a carboxylic acid, a sulfonic acid or an inorganic acid, such asacetic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid,phosphoric acid or the like, to give a compound of formula (17).

In the step (e), a compound of formula (18) may be (1) reduced withreduced iron or zinc under an acidic condition, or 2) reduced with atransition metal catalyst, such as typically palladium, platinum,ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with atransition metal catalyst, such as typically palladium, platinum,ruthenium or nickel, in the presence of formic acid, or 4) reduced withsodium hydrosulfite, to be converted into a compound of formula (19). Acompound of formula (20) can be produced from the compound of formula(19) and the corresponding carboxylic acid or acid anhydride or acidchloride or acid bromide. The compound of formula (20) may be reactedwith a base, such as sodium hydride, lithium diisopropylamide, lithiumhydrogencarbonate, lithium carbonate, lithium hydroxide, sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide, potassiumhydrogencarbonate, potassium carbonate, potassium hydroxide or the like,and with a compound to be represented by R_(1e) Z (where Z represents achlorine atom, a bromine atom, a toluenesulfonyloxy group, or amethanesulfonyloxy group) to give a compound of formula (21).

In the process comprising the above-mentioned step, in general, theproduct may be obtained as a mixture comprising the compound of formula(21) where R_(3e) is positioned in the 5-position and that where it isin the 6-position, or a mixture comprising the compound of formula (21)where R_(3e) is positioned in the 4-position and that where it is in the7-position. Each compound of formula (21) can be purified from themixture as the single compound, for example, through recrystallization,column chromatography, thin-layer chromatography, high-performanceliquid chromatography or the like.

In the step (f), a compound of formula (22) may be 1) reduced withreduced iron or zinc under an acidic condition, or 2) reduced with atransition metal catalyst, such as typically palladium, platinum,ruthenium or nickel, in a hydrogen atmosphere, or 3) reduced with atransition metal catalyst, such as typically palladium, platinum,ruthenium or nickel, in the presence of formic acid, or 4) reduced withsodium hydrosulfite, to be converted into a compound of formula (23). Inthe process 1), the compound of formula (23) is often cyclized in thereaction system directly into a compound of formula (24). Depending onthe compound of formula (22) being reduced, the compound of formula (24)may be partly formed in any of the processes 1) to 4). The compound offormula (23) may be processed with a carboxylic acid, a sulfonic acid oran inorganic acid, such as acetic acid, p-toluenesulfonic acid,hydrochloric acid, sulfuric acid, phosphoric acid or the like, to givethe compound of formula (24). The compound of formula (24) may beconverted into a benzimidazole compound of formula (25) in the samemanner as in the step (e) of converting the compound of formula (20)into the compound of formula (21). In this step, in general, the productmay be obtained as a mixture comprising the compound of formula (25)where R_(3f) is positioned in the 5-position and that where it is in the6-position, or a mixture comprising the compound of formula (25) whereR_(3f) is positioned in the 4-position and that where it is in the7-position. Each compound of formula (25) can be purified from themixture as the single compound, for example, through recrystallization,column chromatography, thin-layer chromatography, high-performanceliquid chromatography or the like.

In the step (g), a compound of formula (26) may be hydrolyzed with abase, such as lithium hydroxide, sodium hydroxide, potassium hydroxideor the like, to give a compound of formula (27). The compound of formula(27) may be reacted with a carbonyldiimidazole and then with amines orsulfonamides in the presence of a base to give different benzimidazolederivatives.

In the step (h), the compound of formula (27) may be processed withthionyl chloride or thionyl bromide or phosphorus trichloride orphosphorus pentachloride or phosphorus oxychloride to be converted intoits acid halide of formula (28). The compound of formula (28) may bereacted with amines or sulfonamides to give different benzimidazolederivatives.

In the step (i), a compound of formula (29) may be reacted with titaniumtetrachloride to give a compound of formula (30).

In the step (j), the compound of formula (27) may be reacted with anazide, such as typically diphenylphosphorylazide, in the presence of analcohol, such as typically t-butanol, to give a compound of formula(31). The compound of formula (31) may be decomposed with an acid togive a compound of formula (32). The compound of formula (32) may bereacted with a compound to be represented by R₄₀ Z (where Z represents achlorine atom or a bromine atom) to give a compound of formula (33).##STR25## wherein R_(g), R_(1a-f) and R_(2a-f) have the same meanings asthose mentioned above; and Z represents a chlorine atom, a bromine atom,a toluenesulfonyloxy group, or a methanesulfonyloxy group. ##STR26##wherein R_(1a-f), R_(2a-f) and Z have the same meanings as thosementioned above. ##STR27## wherein R_(1a-f), R_(2a-f) and R₉ have thesame meanings as those mentioned above. ##STR28## wherein R_(1a-f),R_(2a-f) and R₉ have the same meanings as those mentioned above.

In the step (k), the compound of formula (26) may be reduced into acompound of formula (34), which may be then treated with thionylchloride, thionyl bromide, phosphorus oxychloride, phosphorusoxybromide, phosphorus trichloride, phosphorus pentachloride,methanesulfonyl chloride, toluenesulfonyl chloride or the like to beconverted into a compound of formula (35).

In the step (l), the compound of formula (35) may be reacted with sodiumcyanide or potassium cyanide to give a compound of formula (36), whichmay be then hydrolyzed with lithium hydroxide or sodium hydroxide orpotassium hydroxide to give a carboxylic acid of formula (37).

In the step (m), a compound of formula (38) to be obtained by oxidizingthe compound of formula (34) may be reacted with analkyl(triphenylphosphoranilidene)acetate to give a compound of formula(39), which may then be hydrolyzed with lithium hydroxide or sodiumhydroxide or potassium hydroxide to give a carboxylic acid of formula(40). The compound of formula (35), (37) or (40) may be reacted withamines or sulfonylamides to give different benzimidazole compounds.

In the step (n), the compound of formula (39) may be reduced withpalladium, platinum, ruthenium or the like transition metal catalyst ina hydrogen atmosphere or in the presence of formic acid to give acompound of formula (41).

The following compounds of: ##STR29## where R_(1a-f), R_(2a-f) andR_(3a-f) have the same meanings as those mentioned above; and R_(4a-f)may be selected from the above-mentioned R₄, R₄ ' and R₂₉,

can be produced according to the steps (a) to (f) while starting fromthe following compounds of: ##STR30## where R_(1a), R_(2a) and R_(3a)have the same meanings as those mentioned above; and R_(4a) may beselected from the above-mentioned R₄, R₄ ' and R₂₉ ; ##STR31## whereR_(1b), R_(2b) and R_(3b) have the same meanings as those mentionedabove; and R_(4b) may be selected from the above-mentioned R₄, R₄ ' andR₂₉ ; ##STR32## where R_(1c), R_(2c) and R_(3c) have the same meaningsas those mentioned above; and R_(4c) may be selected from theabove-mentioned R₄, R₄ ' and R₂₉ ; ##STR33## where R_(1d), R_(2d) andR_(3d) have the same meanings as those mentioned above; and R_(4d) maybe selected from the above-mentioned R₄, R₄ ' and R₂₉ ; ##STR34## whereR_(1e), R_(2e) and R_(3e) have the same meanings as those mentionedabove; and R_(4e) may be selected from the above-mentioned R₄, R₄ ' andR₂₉ ; ##STR35## where R_(1f), R_(2f) and R_(3f) have the same meaningsas those mentioned above; and R_(4f) may be selected from theabove-mentioned R₄, R₄ ' and R₂₉.

If desired, the intermediates formed in the above-mentioned steps mayoptionally be purified, prior to being subjected to the next step,through any conventional purification including, for example,recrystallization, column chromatography, thin-layer chromatography,high-performance liquid chromatography and the like. If also desired,the final products of the compounds of the present invention mayoptionally be purified through any conventional purification which isemployed in the art of purifying organic compounds and which includes,for example, recrystallization, column chromatography, thin-layerchromatography, high-performance liquid chromatography and the like. Toidentify these compounds, employable is any of NMR spectrography, massspectrography, IR spectrography, elementary analysis, measurement ofmelting point and others.

Preferred embodiments and their details of various definitions asreferred to herein to be within the scope of the present invention aredescribed below.

Unless otherwise specifically indicated herein, the terminology "lower"indicates that the group has from 1 to 6 carbon atoms. As preferredexamples of the lower alkyl group as referred to herein, mentioned arelinear or branched alkyl groups including a methyl group, an ethylgroup, an n-propyl group, an i-propyl group, an n-butyl group, ani-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, ani-pentyl group, a sec-pentyl group, a t-pentyl group, a 2-methylbutylgroup, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group,a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a2-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutylgroup, a 3,3-dimethylbutyl group, a 1-ethyl-1-methyl propyl groups, etc.

The alkyl group having up to 7 carbon atoms is a linear or branchedalkyl group, including a methyl group, an ethyl group, an n-propylgroup, an i-propyl group, an n-butyl group, an i-butyl group, asec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group,a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexylgroup, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentylgroup, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutylgroup, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group,a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a3-ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl group,a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a4,4-dimethylpentyl group, a 1-propylbutyl group, etc.

The alkyl group having up to 8 carbon atoms is a linear or branchedalkyl group, including a methyl group, an ethyl group, an n-propylgroup, an i-propyl group, an n-butyl group, an i-butyl group, asec-butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group,a sec-pentyl group, a t-pentyl group, a 2-methylbutyl group, an n-hexylgroup, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentylgroup, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutylgroup, a 3-ethylbutyl group, a 1,1-dimethylbutyl group, a2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a1-ethyl-1-methylpropyl group, an n-heptyl group, a 1-methylhexyl group,a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a5-methylhexyl group, a 1-ethylpentyl group, a 2-ethylpentyl group, a3-ethylpentyl group, a 4-ethylpentyl group, a 1,1-dimethylpentyl group,a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a4,4-dimethylpentyl group, a 1-propylbutyl group, an n-octyl group, a1-methylheptyl group, a 2-methylheptyl group, a 3-methylheptyl group, a4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a4-ethylhexyl group, a 5-ethylhexyl group, a 1,1-dimethylhexyl group, a2,2-dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-dimethylhexylgroup, a 5,5-dimethylhexyl group, a 1-propylpentyl group, a2-propylpentyl group, etc.

The lower alkylene group is an alkylene group having 6 or less carbonatoms, including a methylene group, an ethylene group, a propylenegroup, a butylene group, a pentylene group, a hexylene group, etc. Thelower alkenylene group is an alkenylene group having 6 or less carbonatoms, including an ethenylene group, a 1-propenylene group, a2-propenylene group, a 1-butenylene group, a 2-butenylene group, a3-butenylene group, a 1-pentenylene group, a 2-pentenylene group, a3-pentenylene group, a 4-pentenylene group, a 1-hexenylene group, a2-hexenylene group, a 3-hexenylene group, a 4-hexenylene group, a5-hexenylene group, etc.

The halogen atom includes a fluorine atom, a chlorine atom, a bromineatom and an iodine atom. Preferred are a fluorine atom, a chlorine atomand a bromine atom.

The halo-lower alkyl group is a linear or branched alkyl group having upto 8 carbon atoms, which is substituted with one or more halogen atomsselected from fluorine, chlorine, bromine and iodine atoms. Preferred isa linear or branched alkyl group having up to 8 carbon atoms, which issubstituted with one or more halogen atoms selected from fluorine,chlorine and bromine atoms. It includes, for example, a fluoromethylgroup, a difluoromethyl group, a trifluoromethyl group, a chloromethylgroup, a dichloromethyl group, a trichloromethyl group, a bromomethylgroup, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethylgroup, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethylgroup, a 2-chloroethyl group, a 2-bromoethyl group, a 1,2-difluoroethylgroup, a 1,2-dichloroethyl group, a 1,2-dibromoethyl group, a2,2,2-trifluoroethyl group, a heptafluoroethyl group, a 1-fluoropropylgroup, a 1-chloropropyl group, a 1-bromopropyl group, a 2-fluoropropylgroup, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropylgroup, a 3-chloropropyl group, a 3-bromopropyl group, a1,2-difluoropropyl group, a 1,2-dichloropropyl group, a1,2-dibromopropyl group, a 2,3-difluoropropyl group, a2,3-dichloropropyl group, a 2,3-dibromopropyl group, a3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, aperfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, aperfluoroheptyl group, etc.

The lower alkoxy group is a linear or branched alkyloxy group having upto 6 carbon atoms. It includes, for example, a methoxy group, an ethoxygroup, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group,an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group, ann-pentyloxy group, an i-pentyloxy group, a sec-pentyloxy group, at-pentyloxy group, a 2-methylbutoxy group, an n-hexyloxy group, ani-hexyloxy group, a t-hexyloxy group, a sec-hexyloxy group, a2-methylpentyloxy group, a 3-methylpentyloxy group, a 1-ethylbutyloxygroup, a 2-ethylbutyloxy group, a 1,1-dimethylbutyloxy group, a2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a1-ethyl-1-methylpropyloxy group, etc. Preferred are a methoxy group, anethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxygroup, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group,etc.

The lower cycloalkyl group is a cycloalkyl group having from 3 to 7carbon atoms, and preferably includes a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group,etc. More preferred are a cyclopropyl group, a cyclobutyl group, etc.

The lower alkoxy-lower alkyl group is a linear or branched alkyl grouphaving up to 8 carbon atoms, as substituted with a linear or branchedalkyloxy group having up to 8 carbon atoms. For example, this includes amethoxymethyl group, a methoxyethyl group, a methoxypropyl group, amethoxybutyl group, a methoxypentyl group, a methoxyhexyl group, amethoxyheptyl group, a methoxyoctyl group, an ethoxymethyl group, anethoxyethyl group, an ethoxybutyl group, an ethoxypentyl group, anethoxyhexyl group, an ethoxyheptyl group, a ethoxyoctyl group, apropyloxymethyl group, a propyloxyethyl group, a propyloxypropyl group,a propyloxybutyl group, a propyloxypentyl group, an i-propyloxymethylgroup, an i-propyloxyethyl group, an i-propyloxypropyl group, ani-propyloxybutyl group, an i-propyloxypentyl group, a butyloxymethylgroup, a butyloxyethyl group, a butyloxypropyl group, a butyloxybutylgroup, an i-butyloxymethyl group, an i-butyloxyethyl group, ani-butyloxypropyl group, an i-butyloxybutyl group, a sec-butyloxymethylgroup, a sec-butyloxyethyl group, a sec-butyloxypropyl group, asec-butyloxybutyl group, a t-butyloxymethyl group, a t-butyloxyethylgroup, a t-butyloxypropyl group, a t-butyloxybutyl group, apentyloxymethyl group, a pentyloxyethyl group, a pentyloxypropyl group,a pentyloxybutyl group, a hexyloxymethyl group, a hexyloxyethyl group, ahexyloxypropyl group, etc.

The tri-lower alkylsilyl-lower alkyl group is a lower alkyl group, suchas that mentioned hereinabove, to which is bonded a trimethylsilylgroup, a triethylsilyl group, a tripropylsilyl group or the like.

The lower alkylamino group is a linear or branched alkylamino grouphaving up to 6 carbon atoms. This includes, for example, a methylaminogroup, an ethylamino group, an n-propylamino group, an i-propylaminogroup, an n-butylamino group, an i-butylamino group, a sec-butylaminogroup, a t-butylamino group, an n-pentylamino group, an i-pentylaminogroup, a sec-pentylamino group, a t-pentylamino group, a2-methylbutylamino group, an n-hexylamino group, a 1-methylpentylaminogroup, a 2-methylpentylamino group, a 3-methylpentylamino group, a4-methylpentylamino group, a 1-ethylbutylamino group, a2-ethylbutylamino group, a 3-ethylbutylamino group, a1,1-dimethylbutylamino group, a 2,2-dimethylbutylamino group, a3,3-dimethylbutylamino group, a 1-ethyl-1-methylpropylamino group, etc.More preferred are a methylamino group, an ethylamino group, ann-propylamino group, an i-propylamino group, an n-butylamino group, ani-butylamino group, a sec-butylamino group, a t-butylamino group, etc.

The lower alkylthio group is a linear or branched alkylthio group havingup to 6 carbon atoms. This includes, for example, a methylthio group, anethylthio group, an n-propylthio group, an i-propylthio group, ann-butylthio group, an i-butylthio group, a sec-butylthio group, at-butylthio group, an n-pentylthio group, an i-pentylthio group, asec-pentylthio group, a t-pentylthio group, a 2-methylbutylthio group,an n-hexylthio group, an i-hexylthio group, a t-hexylthio group, asec-hexylthio group, a 2-methylpentylthio group, a 3-methylpentylthiogroup, a 1-ethylbutylthio group, a 2-ethylbutylthio group, a1,1-dimethylbutylthio group, a 2,2-dimethylbutylthio group, a3,3-dimethylbutylthio group, a 1-ethyl-1-methylpropylthio group, etc.More preferred are a methylthio group, an ethylthio group, ann-propylthio group, an i-propylthio group, an n-butylthio group, ani-butylthio group, a sec-butylthio group, a t-butylthio group, etc.

The lower alkylthio-lower alkyl group is a linear or branched alkylgroup having up to 6 carbon atoms, such as that mentioned hereinabove,as substituted with a linear or branched alkylthio group having up to 6carbon atoms, such as that mentioned hereinabove.

The lower alkoxycarbonyl group is a linear or branched alkyloxycarbonylgroup with a alkyl moiety having up to 6 carbon atoms. This includes,for example, a methoxycarbonyl group, an ethoxycarbonyl group, ann-propyloxycarbonyl group, an i-propyloxycarbonyl group, ann-butyloxycarbonyl group, an i-butyloxycarbonyl group, asec-butyloxycarbonyl group, a t-butyloxycarbonyl group, ann-pentyloxycarbonyl group, an i-pentyloxycarbonyl group, asec-pentyloxycarbonyl group, a t-pentyloxycarbonyl group, a2-methylbutyloxycarbonyl group, an n-hexyloxycarbonyl group, ani-hexyloxycarbonyl group, a t-hexyloxycarbonyl group, asec-hexyloxycarbonyl group, a 2-methylpentyloxycarbonyl group, a3-methylpentyloxycarbonyl group, a 1-ethylbutyloxycarbonyl group, a2-ethylbutyloxycarbonyl group, a 1,1-dimethylbutyloxycarbonyl group, a2,2-dimethylbutyloxycarbonyl group, a 3,3-dimethylbutyloxycarbonylgroup, a 1-ethyl-1-methylpropyloxycarbonyl group, etc. More preferredare a methoxycarbonyl group, an ethoxycarbonyl group, ann-propyloxycarbonyl group, an i-propyloxycarbonyl group, ann-butyloxycarbonyl group, an i-butyloxycarbonyl group, asec-butyloxycarbonyl group, a t-butyloxycarbonyl group.

The lower alkanoyl group is a linear or branched alkylcarbonyl grouphaving up to 6 carbon atoms. This includes, for example, amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an i-propylcarbonyl group, an n-butylcarbonyl group, an i-butylcarbonylgroup, a sec-butylcarbonyl group, a t-butylcarbonyl group, ann-pentylcarbonyl group, an i-pentylcarbonyl group, a sec-pentylcarbonylgroup, a t-pentylcarbonyl group, a 2-methylbutylcarbonyl group, ann-hexylcarbonyl group, an i-hexylcarbonyl group, a t-hexylcarbonylgroup, a sec-hexylcarbonyl group, a 2-methylpentylcarbonyl group, a3-methylpentylcarbonyl group, a 1-ethylbutylcarbonyl group, a2-ethylbutylcarbonyl group, an 1,1-dimethylbutylcarbonyl group, a2,2-dimethylbutylcarbonyl group, a 3,3-dimethylbutylcarbonyl group, a1-ethyl-1-methylpropylcarbonyl group, etc. More preferred are amethylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group,an i-propylcarbonyl group, an n-butylcarbonyl group, an i-butylcarbonylgroup, a sec-butylcarbonyl group, a t-butylcarbonyl group, etc.

The lower alkanesulfonyl group is a linear or branched alkanesulfonylgroup having up to 6 carbon atoms. This includes, for example, amethanesulfonyl group, an ethanesulfonyl group, a 1-propanesulfonylgroup, a 2-propanesulfonyl group, a 1-butanesulfonyl group, a2-butanesulfonyl group, a 1,1-dimethylethanesulfonyl group, a1-(2-methylpropane)sulfonyl group, a 1-pentanesulfonyl group, a2-pentanesulfonyl group, a 3-pentanesulfonyl group, a1-(3-methylbutane)sulfonyl group, a 1,1-dimethylpropanesulfonyl group, a1-hexanesulfonyl group, a 2-hexanesulfonyl group, a 3-hexanesulfonylgroup, a 1-(2-methylpentane)sulfonyl group, a1-(3-methylpentane)sulfonyl group, a 1-(4-methylpentane)sulfonyl group,a 2-ethylbuthanesulfonyl group, a 3-ethylbutanesulfonyl group, a1,1-dimethylbutanesulfonyl group, a 2,2-dimethylbutanesulfonyl group, a3,3-dimethylbutanensulfonyl group, a 1-ethyl-1-methylpropanesulfonylgroup, etc.

The aryl group includes, for example, a phenyl group, a naphthyl group,etc. The terminology "naphthyl" as referred to herein includes1-naphthyl and 2-naphthyl. The benzene ring or the naphthalene ring inthis group may optionally be substituted by one or more substituentsselected from a halogen atom, a lower alkyl group, a cyano group, anitro group, a trifluoromethyl groups and the like, such as thosementioned hereinabove.

The arylsulfonyl group is a sulfonyl group, to which is bonded an arylgroup such as that mentioned hereinabove, and includes, for example, abenzenesulfonyl group, a toluenesulfonyl group, a naphthalenesulfonylgroup, etc.

The aryl-lower alkyl group is a lower alkyl group, such as thatmentioned hereinabove, to which is bonded an aryl group such as thatmentioned hereinabove, and includes, for example, a benzyl group, a1-phenylethyl group, a 2-phenylethyl group, a phenylpropyl group, aphenylbutyl group, a phenylpentyl group, a phenylhexyl group, anaphthylmethyl group, a naphthylethyl group, a naphthylpropyl group, anaphthylbutyl group, a naphthylpentyl group, a naphthylhexyl group, etc.

The aryl-lower alkyloxy group includes, for example, a benzyloxy group,a 1-phenylethyloxy group, a 2-phenylethyloxy group, a phenylpropyloxygroup, a phenylbutyloxy group, a phenylpentyloxy group, a phenylhexyloxygroup, a naphthylmethyloxy group, a naphthylethyloxy group, anaphthylpropyloxy group, a naphthylbutyloxy group, a naphthylpentyloxygroup, etc., in which the benzene ring or the naphthalene ring mayoptionally be substituted.

The arylsulfonyl-lower alkyl group is a lower alkyl group, such as thatmentioned hereinabove, to which is bonded an arylsulfonyl group such asthat mentioned hereinabove, and includes, for example, abenzenesulfonylmethyl group, a toluenesulfonylmethyl group, anaphthalenesulfonylmethyl group, etc.

The arylsulfonylamino group is an amino group to which is bonded anarylsulfonyl group such as that mentioned hereinabove, and thisincludes, for example, a benzenesulfonylamino group, atoluenesulfonylamino group, a naphthalenesulfonylamino group, etc.

The aryloxy group is an aryl group, such as that mentioned hereinabove,to which is bonded an oxygen atom, and this includes, for example, aphenoxy group, a 1-naphthoxy group, a 2-naphthoxy group, etc.

The arylcarbonyl group is a carbonyl group to which is bonded an arylgroup such as that mentioned hereinabove, and this includes, forexample, a phenylcarbonyl group, a naphthylcarbonyl group, etc.

The arylcarbonylamino group is an amino group to which is bonded anarylcarbonyl group such as that mentioned hereinabove, and thisincludes, for example, a phenylcarbonylamino group, anaphthylcarbonylamino group, etc.

The aryl-lower alkenyl group is an alkenyl group having 6 or less carbonatoms, which is substituted by an aryl group such as that mentionedhereinabove, and this includes, for example, a phenylethenyl group, anaphthylethenyl group, etc.

The heterocyclic group includes, for example, a pyridyl group, aquinolyl group, an isoquinolyl group, a thiazolyl group, a thiadiazolylgroup, a benzofuranyl group, a dibenzofuranyl group, a thianaphthalenylgroup, a 1H-1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolylgroup, a furyl group, a thienyl group, a pyrrolyl group, an imidazolylgroup, a pyrimidinyl group, an indolyl group, a benzimidazolyl group,etc. The heterocyclic group may optionally be substituted by one or moresubstituents of halogen atoms and lower alkyl groups, such as thosementioned hereinabove, and the substituted heterocyclic group of thattype includes, for example, a haloisoquinolyl group, a methylisoquinolylgroup, etc.

The heterocyclic lower alkyl group means a lower alkyl group, such asthat mentioned hereinabove, as substituted by a heterocyclic group, suchas that mentioned hereinabove. This includes, for example, apyridylmethyl group. The halo-heterocyclic lower alkyl group is aheterocyclic lower alkyl group, such as that mentioned hereinabove, inwhich the heterocyclic moiety is substituted with one or more halogens.

The heterocyclic lower alkylamino group is an amino group as substitutedwith a heterocyclic lower alkyl group, such as that mentionedhereinabove, and this includes, for example, a pyridylmethylamino group,etc. The heterocyclic lower alkylcarbamoyl group is a carbamoyl group assubstituted with a heterocyclic lower alkyl group, such as thatmentioned hereinabove, and this includes, for example, apyridylmethylcarbamoyl group, etc.

The terminology "pyridyl" as referred to herein includes 2-pyridyl,3-pyridyl and 4-pyridyl, for which the bonding position is notspecifically defined. The same shall apply to the other heterocyclicgroups as referred to herein, or that is, the bonding positions of theheterocyclic groups as referred to herein are not specifically defined.

The lower alkylenedioxybenzyl group includes, for example, amethylenedioxybenzyl group, an ethylenedioxybenzyl group, apropylenedioxybenzyl group, etc.

A suitable heterocyclic group used herein means a saturated orunsaturated mono- or polycyclic hetero ring containing at least onehetero atom such as an oxygen atom, a sulfur atom, a nitrogen atom, etc.

Preferable examples thereof include the following heterocyclic groups:

7- to 12-membered, preferably 9- or 10-membered unsaturated condensedheterocyclic group (preferably bicyclic group) having 1 to 5 nitrogenatoms, such as indolyl, isoindolyl, indolidinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl,tetrazolopyridazinyl (e.g. tetrazolo[1,5-b]pyridazinyl, etc.),dihydrotriazolopyridazinyl, or the like;

7- to 12-membered, preferably 9- or 10-membered unsaturated condensedheterocyclic group (preferably bicyclic group) having 1 to 3 sulfuratoms or S,S-dioxide thereof, such as dithianaphthalenyl (e.g.4H-1,3-dithianaphthalenyl, 1,4-dithianaphthalenyl, etc.),benzothiophenyl or S,S-dioxide thereof (e.g. benzo[a]thiophenyl orS,S-dioxide thereof, benzo[b]thiophenyl or S,S-dioxide thereof, etc.),or the like;

3- to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,3-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), dihydrotriazinyl (e.g.4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), or thelike;

3- to 8-membered, preferably 5- or 6-membered saturated heteromonocyclic group having 1 to 4 nitrogen atoms, such as azetydinyl,pyrrolidinyl, imidazolydinyl, piperidinyl, pyrazolydinyl, piperadinyl,or the like;

7- to 12-membered, preferably 9- or 10-membered unsaturated condensedheterocyclic group (preferably bicyclic group) having 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms, such as benzooxazolyl,benzooxadiazolyl, or the like;

3- to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms,such as oxazolyl, isooxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), or the like;

3- to 8-membered, preferably 5- or 6-membered saturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms,such as morpholinyl or the like;

7- to 12-membered, preferably 9- or 10-membered unsaturated condensedheterocyclic group (preferably bicyclic group) having 1 to 2 sulfuratoms and 1 to 3 nitrogen atoms, such as benzothiazolyl,benzothiadiazolyl, or the like;

3- to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms,such as thiazolyl, 1,2-thiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), orthe like;

3- to 8-membered, preferably 5- or 6-membered saturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms,such as thiazolydinyl;

3- to 8-membered, preferably 5- or 6-membered unsaturated heteromonocyclic group having one sulfur atom, such as thienyl or the like;etc.

Suitable "esterified carboxyl groups" are exemplified below.

The ester portion of the esterified carboxyl group suitably include alower alkyl ester, such as methyl ester, ethyl ester, propyl ester,isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester,pentyl ester, or hexyl ester, which may have at least one appropriatesubstituent. Examples of the lower alkyl ester include loweralkanoyloxy(lower)alkyl ester, such as acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxy methyl ester, 1-(or2-)acetoxyethyl ester, 1-(2-, or 3-)acetoxypropyl ester, 1-(2-, 3- or4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(2-, or3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1(or2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or2-)hexanoyloxyethyl ester, isobutyryloxymethyl ester,2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, or1-(or 2-)pentanoyloxyethyl ester, lower alkanesulfonyl(lower)alkylester, such as 2-mesylethyl ester, mono(di, or tri)halo(lower)alkylester, such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, loweralkoxycarbonyloxy(lower)alkyl ester, such as methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,tertiary-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethylester, 1-(or 2-)ethoxycarbonyloxyethyl ester, or 1-(or2-)isopropoxycarbonyloxyethyl ester, phthalizilidene(lower)alkyl esteror (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester, such as(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, lower alkenyl ester, suchas vinyl ester or allyl ester, lower alkynyl ester, such as ethynylester or propinyl ester, ar(lower)alkyl ester which may have at leastone appropriate substituent, such as benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, or4-hydroxy-3,5-di-tertiary-butylbenzyl ester, aryl ester which may haveat least one appropriate substituent, such as phenyl ester,4-chlorophenyl ester, tolyl ester, tertiary-butylphenyl ester, xylylester, mesityl ester, or cumenyl ester, phthalidyl ester, etc.

Preferable examples of a carboxyl groups protected by esterificationinclude lower alkoxycarbonyl and phenyl(or nitrophenyl) (C₁-C₄)alkoxycarbonyl. Most preferred are methoxycarbonyl, ethoxycarbonyl,and benzyloxycarbonyl.

Suitable amidated carboxyl groups include the following:

a carbamoyl group;

a mono- or di-lower alkyl carbamoyl group (as a lower alkyl group, thoseas described above can be used), such as methylcarbamoyl,dimethylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl,t-butylcarbamoyl, N-methyl-N-(pyridylmethyl)carbamoyl, or the like;

an aryl(lower alkyl)carbamoyl (as an aryl group and a lower alkyl group,those as described above can be used), such as benzylcarbamoyl,3,4-methylenedioxybenzylcarbamoyl, diaminobenzylcarbamoyl, orphenethylcarbamoyl;

a cyclo(lower alkyl)carbamoyl having 3 to 7 carbon atoms (as a cyclolower alkyl group, those as described above can be used), such ascyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl or the like;

an arylcabamoyl group (as an aryl group, those as described above can beused), such as phenylcarbamoyl, naphthylcarbamoyl, or the like;

a heterocyclic carbamoyl group (as a heterocyclic group, those asdescribed above can be used), such as thiazolylcarbamoyl,thiadiazolylcarbamoyl, pyridyl-carbamoyl, triazolylcarbamoyl,tetrazolylcarbamoyl, N-methyl-N-pyridinecarbamoyl, morpholinocarbamoyl,or the like;

a heterocyclic(lower alkyl)carbamoyl group (as a heterocyclic loweralkyl group, those as described above can be used), such asmorpholinoethylcarbamoyl, pyridylmethylcarbamoyl,methylenedioxybenzylcarbamoyl, or the like;

an N-di-substituted carbamoyl group containing nitrogen as a member of anitrogen-containing heterocyclic ring, such as morpholinocarbonyl,thiomorpholinocarbonyl, 1-perhydroazepinylcarbonyl,1,1-dioxothiazolydinecarbonyl, piperidinocarbonyl,1-piperazinylcarbonyl, 4-(2-hydroxyethyl)-1-piperazinylcarbonyl,4-methyl-1-piperazinylcarbonyl, carboxypyrrolidinocarbonyl, or the like;

a substituted sulfonylcarbomoyl group, etc.

The substituent for the substituted sulfonyl-carbamoyl group includesthe above-described groups such as the alkyl group having carbon atomsup to 8, the halo lower alkyl group, the aryl lower alkyl group, thehydroxy-lower alkyl group, the tri(lower alkyl)silyl(lower alkyl) group,the lower alkoxy-lower alkyl group, the lower alkylthio-lower alkylgroup, the heterocyclic group, the aryl group, and the like. The arylgroup may be substituted by a halogen atom, a lower alkyl group a halolower alkyl group, a lower alkoxy group, a nitro group, or the like.Specific examples of the substituted sulfonylcarbamoyl group includenaphthylsulfonylcarbamoyl, benzenesulfonylcarbamoyl,nitrobenzenesulfonylcarbamoyl, trihalobenzenesulfonylcarbamoyl, loweralkoxybenzenesulfonylcarbamoyl, halobenzenesulfonylcarbamoyl, mono- ordi-(lower alkyl)benzenesulfonylcarbamoyl, alkanesulfonylcarbamoyl having1 to 8 carbon atoms, such as t-butylsulfonylcarbamoyl,butylsulfonylcarbamoyl, propylsulfonylcarbamoyl,isopropylsulfonylcarbamoyl, methylsulfonylcarbamoyl,octylsulfonylcarbamoyl, pentylsulfonylcarbamoyl,isopentylsulfonylcarbamoyl, hexylsulfonylcarbamoyl, or the like,trihalo(lower)alkylsulfonylcarbamoyl,phenyl(lower)alkylsulfonylcarbamoyl, tri(lower)alkylsulfonylcarbamoyl,lower alkylthio(lower)alkylsulfonylcarbamoyl, loweralkoxy(lower)alkylsulfonylcarbamoyl, quinolinesulfonylcarbamoyl, or thelike.

Suitable acyl groups include aliphatic acyl, aromatic acyl, heterocyclicacyl, and aliphatic acyl substituted with an aromatic group or aheterocyclic group, which are derived from carboxylic acid, carbonicacid, sulfonic acid, carbamic acid, and the like.

Examples of the aliphatic acyl include saturated or unsaturatednon-cyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl(e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.),carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl,etc.), alkoxycarbonyl such as lower alkoxy carbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,tertiary-butoxycarbonyl, etc.), alkenyloxycarbonyl such as loweralkenyloxycarbonyl (e.g. vinyloxycarbonyl, allyloxycarbonyl, etc.),alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl,chlotonoyl, etc.), cycloalkanecarbonyl such ascyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl, etc.) and the like.

Examples of the aromatic acyl include C₆ -C₁₀ aroyl (e.g. benzoyl,toluoyl, xyloyl, etc.), N-(C₆ -C₁₀)arylcarbamoyl (e.g.N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C₆ -C₁₀arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.), and the like.

Examples of the heterocyclic acyl include heterocyclic carbonyl,heherocyclic (lower)alkanoyl (e.g. heterocyclic acetyl, heterocyclicpropanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclichexanoyl, etc.), heterocyclic(lower)alkenoyl (e.g. heterocyclicpropenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclichexenoyl, etc.) heterocyclic glyoxyloyl, heterocyclic sulfinyl,heterocyclic sulfonyl, etc.

The aromatic group-bound aliphatic acyl includes aralkoxycarbonyl suchas phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl,phenethyloxycarbonyl, etc.).

These acyl groups may be substituted with one or more appropriatesubstituent, such as a nitro group. An example thereof isnitroaralkoxycarbonyl (e.g. nitrobenzyloxy-carbonyl, etc.).

Preferred salts of the benzimidazole derivatives of the presentinvention are non-toxic, ordinary pharmaceutically acceptable saltsthereof. For example, mentioned are salts of the derivatives with basesas well as acid-addition salts of the derivatives, which include, forexample, salts thereof with inorganic bases, such as salts with alkalimetals (e.g., sodium, potassium); salts with alkaline earth metals(e.g., calcium, magnesium); ammonium salts; salts with organic amines(e.g., triethylamine, pyridine, picoline, ethanolamine, triethanolamine,dicyclohexylamine, N,N'-dibenzylethylenediamine); salts with inorganicacids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid); salts with organic carboxylic acids (e.g., formicacid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid);salts with sulfonic acids (e.g., methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid); salts with basic or acidic amino acids(e.g., arginine, aspartic acid, glutamic acid), etc.

The compounds of the invention could contain one or more chiral centers,therefore they could be enantiomers or diastereomers. Few of thecompounds containing alkenyl group could also be cis- or trans-isomers.In both cases, each of such isomers as well as the mixture thereof arewithin the scope of this invention.

The compounds of the invention can also exist as tautomers, andindividual of such tautmers and the mixture thereof are within the scopeof this invention.

The compounds of the invention and their salts can be solvate, which arealso within the invention. The solvent for the solvate is preferablywater or ethanol.

Specific examples of benzimidazole derivatives of formula (IX) include6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole,5-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole,5-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(1-octanesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(2-propanesufonylcarbamoyl)benzimidazole,1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole,5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole,6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole,N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acrylamide,N-benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acetamide,1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalenesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalenesulfonylcarbamoyl)benzimidazole,6-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole,6-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(α-toluenesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-6-(2,5-dimethylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)benzenesulfonylcarbamoyl]benzimidazole,6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole,5-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-hydroxybenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylaminobenzimidazole,2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-heptylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxymethylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-i-propylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthiobenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylthiobenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylthiobenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthiobenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole,6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole,6-benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)benzimidazole,6-benzenesulfonylcarbamoyl-2-methyl-1-benzylbenzimidazole,6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazole,6-benzenesulfonyl-carbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole,6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole,N-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]propionamide,6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(8-quinolinesulfonylcarbamoyl)benzimidazole,6-(4-t-butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole,5-benzenesulfonylcarbamoyl-2-methylbenzimidaozle,1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole,1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)benzimidazole,6-ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]benzimidazole,1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole,7-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(2-chlorobenzyl)-2-methyl-6-[1-[3-(trimethylsilyl)propane]sulfonylcarbamoyl]benzimidazole,4-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-(1-ethanesulfonyl-carbamoyl)-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,1-(2-chlorobenzyl)-6-[(2-methoxyethane)sulfonylcarbamoyl]-2-methylbenzimidazole,1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-2-methyl(1-pentanesulfonylcarbamoyl)benzimidazole,1-(biphenyl-4-ylmethyl)-2-ethyl-6-[1-[3-(methylthio)propane]sulfonylcarbamoyl]benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-[1-(3-methyl)butanesulfonylcarbamoyl]benzimidazole,5-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(4-biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxyethanesulfonylcarbamoyl)benzimidazole,6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(4-phenoxybenzyl)benzimidazole,6-(butanesulfonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)benzimidazole,1-[(4-benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethyl)benzyl]benzimidazole,1-[(4-benzoyl)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole,1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole,6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole,and6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole,etc.

Specific examples of compounds of formula (X) include1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,6-ethoxycarbonyl-2-N-propyl-1-(2-pyridylmethyl)benzimidazole,6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole,1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole,6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole,6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole,1-[2-(benzenesulfonylmethyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole,1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole,1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methyl-benzimidazole,6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole,1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole,6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole,2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole,6-carboxy-1-methyl-2-n-propylbenzimidazole,6-carboxy-2-n-propyl-1-i-propylbenzimidazole,1-n-butyl-6-carboxy-2-n-propylbenzimidazole,6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole,1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole,6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole,6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole,6-carboxy-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]benzimidazole,6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole,6-carboxy-1-(biphenyl-2-ylmethyl)-2-methylbenzimidazole,6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole,1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole,5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole,1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole,1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole,5-ethoxycarbonyl-2-methylbenzimidazole,2-benzyl-5-ethoxycarbonylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole,5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole,5-ethoxycarbonyl-2-trifluoromethylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole,1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole,1-methyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-n-propyl-1-i-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-n-butyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-benzyl-1-methyl-6- (2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole,2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-benzenesulfonyl-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-phenylethyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)aminomethyl]benzimidazole,2-benzyl-6-carboxy-1-methylbenzimidazole,4-ethoxycarbonyl-2-methylbenzimidazole,1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,1-(4-benzyloxybenzyl)-6-carboxy-2-methylbenzimidazole,6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-carboxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole,1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole,6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole,6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole,1-[4-(3,4-dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole,6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole,1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethylbenzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-ylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(2-pyridylcarbamoyl)benzimidazole,1-[sec-(2,4-dichlorophenethyl)]-6-ethoxycarbonyl-2-methylbenzimidazole,6-carboxy-1-[sec-(2,4-dichlorophenethyl)]-2-methylbenzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-ylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-(1,3,4-triazol-2-ylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(3-pyridylcarbamoyl)benzimidazole,1-(4-biphenylmethyl)-2-ethyl-6-(4-pyridylcarbamoyl)benzimidazole,1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole,6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)benzimidazole,6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole,6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole,6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole,6-ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)benzimidazole,1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole,1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole,6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole,6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole,1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole,1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole,6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole,1-(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole,6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole,6-carboxy-2-methyl-(2-quinolylmethyl)-benzimidazole,1-(2,4-dichlorobenzyl)-2-hydroxy-6-ethoxycarbonylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole,and 6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)methyl]benzimidazole, etc.

Specific examples of benzimidazole derivatives of formula (XI) include1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenylbenzimidazole,2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole,2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole,2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)benzimidazole,2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole,2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole,2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole,2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole,2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole,1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid, methyl1-(2-chlorobenzyl)-2-methyl-benzimidazole-6-acrylate,1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid,1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]benzimidazole,1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethyl-benzimidazole,1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole,1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole,1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethyl-benzimidazole,and 6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethyl benzimidazole, etc.

Specific examples of benzimidazole derivatives of formula (XII) include6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole,6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole,6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole,6-t-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole, and6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-2-methylbenzimidazole, etc.

Specific examples of benzimidazole derivatives of formula (XIII) include1-(2-chlorobenzyl)-6-cyano-2-cyclopropylbenzimidazole, and1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole, etc. Specificexamples of benzimidazole derivatives of formula (VI) include1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-2-n-propyl-6-thiomorpholinocarbonylbenzimidazole,1-(2-chlorobenzyl)-2-cyclopropyl-6-(2-pyridylcarbamoyl)benzimidazole,6-(2-carboxy-1-pyrrolidinocarbonyl)-1-(2-chlorobenzyl)-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-6-piperonylcarbamoyl-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-6-(homopiperidinocarbonyl)-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-6-[N-methyl-N-(2-pyridyl)carbamoyl]-2-n-propylbenzimidazole,2-n-butyl-1-(2-(fluorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]benzimidazole,2-cyclopropyl-1-(2-fluorobenzyl)-6-(piperonylcarbamoyl)benzimidazole,2-[[1-(2-chlorobenzyl)-2-ethylbenzimidazol-6-yl]carbonylaminomethyl]pyridine-1-oxide,and 1-(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)benzimidazole,etc.

The present invention further includes, within its scope, the followingnovel benzimidazole derivatives:1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propylbenzimidazole,6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propylbenzimidazole,6-ethoxycarbonyl-1-(3-fluorobenzyl)-2-n-propylbenzimidazole,1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,1-(3-methylbenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,2-cyclopropyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)-benzimidazole,1-(2-chlorobenzyl)-2-cyclobutyl-6-ethoxycarbonylbenzimidazole,1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-n-pentylbenzimidazole,5-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole,6-carboxy-1-(3-methylbenzyl)-2-n-propylbenzimidazole,2-n-butyl-7-carboxy-1-(2-chlorobenzyl)benzimidazole,6-carboxy-1-(2-fluorobenzyl)-2-cyclopropylbenzimidazole,2-n-butyl-6-carboxy-1-(2-fluorobenzyl)benzimidazole,1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazole,1-(2-chlorobenzyl)-6-morpholinocarbamoyl-2-n-propylbenzimidazole,2-n-butyl-1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-n-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole,1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole,1-(2-chlorobenzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl)-2-cyclobutyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl)-2-n-propyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl)-6-phenylcarbamoyl-2-n-propylbenzimidazole,1-(2-chlorobenzyl)-2-n-propyl-6-[(4-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl)-2-n-propyl-6-[(3-pyridylmethyl)carbamoyl]benzimidazole,1-(3-methylbenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl )-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-n-butyl-1-(2-chlorobenzyl)-7-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-n-butyl-1-(2-fluorobenzyl)-6-(2-pyridylmethylcarbamoyl)benzimidazole,1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole,1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole,6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole,1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole,1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole,1-(4-t-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole,1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole,6-carboxy-1-(4-chlorobenzyl)-2-n-propylbenzimidazole,6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole,6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole,6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole,6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole,1-benzyl-6-carboxy-2-n-propylbenzimidazole,6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole,6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(4-t-butylbenzyl)-6-carboxy-2-methylbenzimidazole,6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole,1-benzyl-6-carboxy-2-methylbenzimidazole,5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole,6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2-chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(3-chlorobenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-benzyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[2-(trifluoromethyl)benzyl]benzimidazole,2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]benzimidazole,1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,2-methyl-1-(2-methylbenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-benzyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(4-t-butylbenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole,7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole,4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole,5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, and6-(n-butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole.

The benzimidazole derivatives and their pharmaceutically acceptablesalts of the present invention that are mentioned hereinabove areeffective for preventing and treating various disorders of, for example,impaired glucose tolerance, diabetes (type II diabetes), diabeticcomplications (e.g., diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, etc.), syndrome of insulin resistance (e.g., insulinreceptor disorders, Rabson-Mendenhall syndrome, leprechaunism,Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushingsyndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis,cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.),hyperglycemia (e.g., abnormal saccharometabolism such as feedingdisorders, etc.), and hypertension based on their blood sugarlevel-depressing activity, as well as stenocardia, hypertension,pulmonary hypertension, congestive heart failure, glomerulopathy (e.g.,diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g.,renopathy induced by FK506, cyclosporin, etc.), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),distal angiopathy, cerebral apoplexy, chronic reversible obstructions(e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.),allergic rhinitis, urticaria, glaucoma, diseases characterized byenteromotility disorders (e.g., hypersensitive enteropathy syndrome,etc.), impotence (e.g., organic impotence, psychic impotence, etc.), anddiabetic complications (e.g., diabetic gangrene, diabetic arthropathy,diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerouscachexia, and restenosis after PTCA based on their cGMP-PDE (especiallyPDE-V)-inhibiting activity, smooth muscle relaxing activity,bronchodilating activity, vasodilating activity, smooth muscle cellsuppressing activity, and antiallergic activity.

In addition, we, the present inventors, have further found that thebenzimidazole derivatives which we have disclosed in Japanese PatentApplication Laid-Open No. 5-222000 as c-GMP phosphodiesterase inhibitorsalso have the above-mentioned activities, and have now confirmed thatthese benzimidazole derivatives are also effective for preventing andtreating the above-mentioned diseases and disorders like the compoundsmentioned hereinabove.

Accordingly, the present invention further includes pharmaceuticalcompositions comprising, as an active ingredient, any of benzimidazolederivatives of the following formula (I) and their pharmaceuticallyacceptable salts, which are effective for preventing and treatingimpaired glucose tolerance, diabetes (type II diabetes), diabeticcomplications (e.g., diabetic nephropathy, diabetic neuropathy, diabeticretinopathy, etc.), syndrome of insulin resistance (e.g., insulinreceptor disorders, Rabson-Mendenhall syndrome, leprechaunism,Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushingsyndrome, acromegaly, etc.), hyperlipidemia, atherosclerosis,cardiovascular disorders (e.g., stenocardia, cardiac failure, etc.),hyperglycemia (e.g., abnormal saccharometabolism such as feedingdisorders, etc.), or hypertension; or stenocardia, hypertension,pulmonary hypertension, congestive heart failure, glomerulopathy (e.g.,diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g.,renopathy induced by FK506, cyclosporin, etc.), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),distal angiopathy, cerebral apoplexy, chronic reversible obstructions(e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.),allergic rhinitis, urticaria, glaucoma, diseases characterized byenteromotility disorders (e.g., hypersensitive enteropathy syndrome,etc.), impotence (e.g., organic impotence, psychic impotence, etc.), anddiabetic complications (e.g., diabetic gangrene, diabetic arthropathy,diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerouscachexia, or restenosis after PTCA. ##STR36## In formula (I): R₁represents a hydrogen atom, an arylsulfonyl group, or a lower alkylgroup; and said lower alkyl group may be substituted by an aryl group oran aryl group substituted by one or two substituents selected from ahalogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkylgroup, a lower alkoxy group, a nitro group, an amino group, a cyanogroup, an aryl group, an aryl-lower alkyl group, an aryl-lower alkyloxygroup, a haloaryl-lower alkyloxy group, an arylsulfonyl-lower alkylgroup, an arylsulfonylamino group, a cyanoaryl group, and a heterocyclicgroup, or by a heterocyclic group;

R₂ represents a hydrogen atom, a lower cycloalkyl group, a hydroxylgroup, a lower alkoxy group, a mercapto group, a lower alkylthio group,an amino group, a lower alkylamino group, a carboxyl group, an arylgroup, or a lower alkyl group; and said lower alkyl group may besubstituted by a halogen atom, a lower alkoxy group, a cyano group, achlorocarbonyl group, an aryl group, or a heterocyclic group;

R₃ represents a carboxyl group, an esterified carboxyl group, anamidated carboxyl group, an amino group, an amido group, or a sulfonylgroup; and said amino group and said amido group may be substituted byan acyl group or a sulfonyl group; and a halogen atom, an amino group,or an acylamino group is bonded to said sulfonyl group; or R₃ may bebonded to the skeleton via a lower alkylene or alkenylene group; and

R₄ represents a neutral substituent. R₄ includes a halogen atom, and alower alkyl group, an aralkyl group, an alkynyl group, a lower alkyloxygroup, and halogen-substituted groups of these. Where R₄ is ahydrocarbon group, it may be either saturated or unsaturated, or eitherlinear or cyclic, or may even be branched. For the halogen atom and thehalogen-substituted groups, the kind of the halogen is not specificallydefined. For the latter, the number of halogens substituted is notspecifically defined.

n means an integer from 0 to 3. Thus, one, two or three R₄ s may bebonded to the skeleton, or no R₄ may be bonded thereto. The position ofR₄ may be any of the ortho-position, the meta-position and thepara-position relative to the other substituent.

Specific examples of benzimidazole derivatives of formula (I) include2-butyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole,1-(4-bromo-2-fluorobenzyl)-2-butyl-6-ethoxycarbonylbenzimidazole,2-butyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole,2-butyl-6-ethoxycarbonyl-1-(4-methoxycarbonylbenzyl)benzimidazole,2-butyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)benzimidazole,2-butyl-6-ethoxycarbonyl-1-(2-trifluoromethylbenzyl)benzimidazole,1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-ethylbenzimidazole,1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-propylbenzimidazole,1-(2-chlorobenzyl)-2-cyclopropyl-6-ethoxycarbonylbenzimidazole,1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-isopropylbenzimidazole,2-butyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole,2-butyl-1-(2-chlorobenzyl)-7-ethoxycarbonylbenzimidazole,1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-propylbenzimidazole,2-butyl-1-(2-chlorobenzyl)-6-carboxybenzimidazole,2-butyl-6-carboxy-1-(4-carboxybenzyl)benzimidazole,6-carboxy-1-(2-chlorobenzyl)-2-ethylbenzimidazole,6-carboxy-1-(2-chlorobenzyl)-2-propylbenzimidazole,6-carboxy-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole,2-butyl-5-carboxy-1-(2-chlorobenzyl)imidazole,2-butyl-1-(2-chlorobenzyl)-6-dimethylcarbamoylbenzimidazole,6-(benzylcarbamoyl)-2-butyl-1-(2-chlorobenzyl)benzimidazole,2-butyl-1-(2-chlorobenzyl)-6-morpholinocarbonylbenzimidazole,2-butyl-6-carbamoyl-(2-chlorobenzyl)-benzimidazole,2-butyl-1-(2-chlorobenzyl)-6-(4-methylpiperazinyl)carbonylbenzimidazole,2-butyl-1-(2-chlorobenzyl)-6-(methylcarbamoyl)benzimidazole,6-carbamoyl-1-(2-chlorobenzyl)-2-ethylbenzimidazole,6-carbamoyl-1-(2-chlorobenzyl)-2-propylbenzimidazole,6-carbamoyl-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole,2-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole,2-butyl-1-(2-chlorobenzyl)-6-(isopropylcarbonyl)benzimidazole,1-(2-chlorobenzyl)-6-chloroformyl-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(methylcarbamoyl)-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(ethylcarbamoyl)-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(isopropyl)carbamoyl-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(piperidinocarbonyl)-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(morpholinocarbonyl)-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-(2-morpholinoethyl)carbamoyl-2-propylbenzimidazole,1-(2-chlorobenzyl)-6-[4-(2-hydroxyethyl)piperazinyl]carbonyl-2-propylbenzimidazole,1-(2-chlorobenzyl)-2-propyl-6-(2-pyridylmethyl)carbamoylbenzimidazole,1-(2-chlorobenzyl)-2-propyl-6-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]carbamoylbenzimidazole,etc.

To use the benzimidazole derivatives of the present invention fortreating diseases or disorders such as those mentioned hereinabove, theymay be formulated into pharmaceutical compositions of ordinary forms,which comprise, as an active ingredient, any of the derivatives alongwith pharmaceutically acceptable carriers, such as organic or inorganicsolid or liquid vehicles, and which are suitable for peroraladministration, parenteral administration or external application. Thepharmaceutical compositions may be of any solid form of tablets,granules, powders, capsules, etc., or may be of any liquid form ofsolutions, suspensions, syrups, emulsions, lemonades, etc.

If desired, the pharmaceutical compositions may further contain apharmaceutical aid, a stabilizer, a wetting agent, and also any ordinaryadditive of, for example, lactose, citric acid, tartaric acid, stearicacid, magnesium stearate, terra alba, sucrose, corn starch, talc,gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethyleneglycol, etc.

The amount of the above-mentioned derivative of the present invention tobe used shall vary, depending on the age and the condition of patients,the type and the condition of diseases or disorders, and the type of thederivative to be used. In general, for peroral administration, the doseof the derivative may be from 1 to 100 mg/kg; and for intramuscularinjection or intravenous injection, it may be from 0.1 to 10 mg/kg. Sucha unit dose may be applied to a patient once to four times a day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows chemical formulae of compound (42) to compound (47).

FIG. 2 shows chemical formulae of compound (48) to compound (53).

FIG. 3 shows chemical formulae of compound (54) to compound (59).

FIG. 4 shows chemical formulae of compound (60) to compound (65).

FIG. 5 shows chemical formulae of compound (66) to compound (71).

FIG. 6 shows chemical formulae of compound (72) to compound (77).

FIG. 7 shows chemical formulae of compound (78) to compound (83).

FIG. 8 shows chemical formulae of compound (84) to compound (89).

FIG. 9 shows chemical formulae of compound (90) to compound (95).

FIG. 10 shows chemical formulae of compound (96) to compound (101).

FIG. 11 shows chemical formulae of compound (102) to compound (107).

FIG. 12 shows chemical formulae of compound (108) to compound (113).

FIG. 13 shows chemical formulae of compound (114) to compound (119).

FIG. 14 shows chemical formulae of compound (120) to compound (125).

FIG. 15 shows chemical formulae of compound (126) to compound (131).

FIG. 16 shows chemical formulae of compound (132) to compound (137).

FIG. 17 shows chemical formulae of compound (138) to compound (143).

FIG. 18 shows chemical formulae of compound (144) to compound (149).

FIG. 19 shows chemical formulae of compound (150) to compound (155).

FIG. 20 shows chemical formulae of compound (156) to compound (161).

FIG. 21 shows chemical formulae of compound (162) to compound (167).

FIG. 22 shows chemical formulae of compound (168) to compound (173).

FIG. 23 shows chemical formulae of compound (174) to compound (179).

FIG. 24 shows chemical formulae of compound (180) to compound (185).

FIG. 25 shows chemical formulae of compound (186) to compound (191).

FIG. 26 shows chemical formulae of compound (192) to compound (197).

FIG. 27 shows chemical formulae of compound (198) to compound (203).

FIG. 28 shows chemical formulae of compound (204) to compound (209).

FIG. 29 shows chemical formulae of compound (210) to compound (215).

FIG. 30 shows chemical formulae of compound (216) to compound (221).

FIG. 31 shows chemical formulae of compound (222) to compound (227).

FIG. 32 shows chemical formulae of compound (228) to compound (233).

FIG. 33 shows chemical formulae of compound (234) to compound (239).

FIG. 34 shows chemical formulae of compound (240) to compound (245).

FIG. 35 shows chemical formulae of compound (246) to compound (251).

FIG. 36 shows chemical formulae of compound (252) to compound (257).

FIG. 37 shows chemical formulae of compound (258) to compound (263).

FIG. 38 shows chemical formulae of compound (264) to compound (269).

FIG. 39 shows chemical formulae of compound (270) to compound (275).

FIG. 40 shows chemical formulae of compound (276) to compound (281).

FIG. 41 shows chemical formulae of compound (282) to compound (287).

FIG. 42 shows chemical formulae of compound (288) to compound (293).

FIG. 43 shows chemical formulae of compound (294) to compound (299).

FIG. 44 shows chemical formulae of compound (300) to compound (305).

FIG. 45 shows chemical formulae of compound (306) to compound (311).

FIG. 46 shows chemical formulae of compound (312) to compound (316).

FIG. 47 shows chemical formulae of compound (317) to compound (322).

FIG. 48 shows chemical formulae of compound (323) to compound (328).

FIG. 49 shows chemical formulae of compound (329) to compound (334).

FIG. 50 shows chemical formulae of compound (335) to compound (340).

FIG. 51 shows chemical formulae of compound (341) to compound (346).

FIG. 52 shows chemical formulae of compound (347) to compound (352).

FIG. 53 shows chemical formulae of compound (353) to compound (358).

FIG. 54 shows chemical formulae of compound (359) to compound (364).

FIG. 55 shows chemical formulae of compound (365) to compound (370).

FIG. 56 shows chemical formulae of compound (371) to compound (376).

FIG. 57 shows chemical formulae of compound (377) to compound (382).

FIG. 58 shows chemical formulae of compound (383) to compound (386).

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated more specifically by referring tothe following Examples. However, the present invention is not limitedthereto.

PRODUCTION EXAMPLE 1 Production of ethyl3-[N-(2-bromobenzyl)butyrylamino]-4-nitrobenzoate

One-hundred milligrams of sodium hydride (60% water-in-oil suspension)were added to a solution of 247 mg of ethyl3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide in anitrogen atmosphere at room temperature in some divided portions. Thereaction suspension was stirred at the same temperature for 1 hour, anda solution of 244 mg of 2-bromobenzyl bromide in 2 ml ofN,N-dimethylformamide was gradually added dropwise thereto over a periodof 10 minutes. The reaction mixture was stirred at room temperature for1 hour, and was poured in ice water. The oily substance precipitated wasextracted with methylene chloride. The organic solvent layer was washedwith water, dried, and then concentrated under reduced pressure. Theresidue was developed through silica-gel flash column chromatography,and was eluted with a mixture of 25% ethyl acetate and n-hexane to give540 mg of yellow oil of ethyl3-[N-(2-bromobenzyl)butyrylamino-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 0.87 (3H, t, J=8 Hz), 1.48 (3H, t, J=8 Hz), 1.68(2H, sextet, J=8 Hz), 2.03 (2H, t, J=8 Hz), 4.30-4.46 (2H, m), 4.70 (1H,d, J=15 Hz), 5.40 (1H, d, J=15 Hz), 7.08-7.34 (2H, m), 7.43 (1H, dd,J=1, 8 Hz), 7.58 (1H, dd, J=1, 8 Hz), 7.66 (1H, d, J=1 Hz), 7.96 (1H, d,J=8 Hz 8.16 (1H, dd, J=1, 8 Hz).

PRODUCTION EXAMPLE 2 Production of ethyl3-[N-(2-chlorobenzyl)benzoylamino]-4-nitrobenzoate

In the same manner as in Production Example 1, 480 mg of yellow crystalsof ethyl 3-[N-(2-chlorobenzyl)benzoylamino]-4-nitrobenzoate were formedfrom 450 mg of ethyl 3-benzoylamino-4-nitrobenzoate and 243 mg of2-chlorobenzyl bromide.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 1.35 (3H, t, J=8 Hz), 4.35 (2H, q, J=8 Hz), 4.76(1H, bd, J=15 Hz), 5.82 (1H, bd, J=15 Hz), 7.10-8.00 (12H, m).

mp: 111-113° C.

PRODUCTION EXAMPLE 3 Production of ethyl3-[N-(2-fluorobenzyl)butyrylamino]-4-nitrobenzoate

In the same manner as in Production Example 1, 394 mg of yellow oil ofethyl 3-[N-(2-fluorobenzyl)butyrylamino]-4-nitrobenzoate were formedfrom 300 mg of ethyl 3-butyrylamino-4-nitrobenzoate and 243 mg of2-fluorobenzyl bromide.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 0.85 (3H, t, J=8 Hz), 1.40 (3H, t, J=8 Hz), 1.65(2H, sextet, J=8 Hz), 1.98 (2H, t, J=8 Hz), 4.30-4.45 (2H, m), 4.60 (1H,d, J=10 Hz), 5.25 (1H, d, J=10 Hz), 6.88 (2H, t, J=8 Hz), 7.08 (2H, dd,J=5, 8 Hz), 7.24 (1H, dt, J=1, 8 Hz), 7.41 (1H, dt, J=1, 8 Hz), 7.69(1H, d, J=1 Hz), 7.96 (1H, d, J=8 Hz), 8.15 (1H, dd, J=1, 8 Hz).

PRODUCTION EXAMPLE 4 Production of ethyl3-[N-(4-fluorobenzyl)butyrylamino]-4-nitrobenzoate

In the same manner as in Production Example 1, 400 mg of yellow oil ofethyl 3-[N-(4-fluorobenzyl)butyrylamino]-4-nitrobenzoate were formedfrom 300 mg of ethyl 3-butyrylamino-4-nitrobenzoate and 243 mg of4-fluorobenzyl bromide.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 0.86 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz),1.56-1.76 (2H, m), 1.96-2.04 (2H, m), 4.32-4.46 (2H, m), 4.40 (1H, d,J=14 Hz), 5.23(1H, d, J=14 Hz), 6.95 (2H, t, J=8 Hz), 7.10 (2H, dd, J=5,8 Hz), 7.47 (1H, d, J=1 Hz), 7.95 (1H, d, J=8 Hz), 8.16 (1H, dd, J=1, 8Hz).

PRODUCTION EXAMPLE 5 Production of ethyl3-[N-(2-cyanobenzyl)butyrylamino]-4-nitrobenzoate

Potassium carbonate (296 mg) was added to a solution of 200 mg of ethyl3-butyrylamino-4-nitrobenzoate and 154 mg of 2-cyanobenzyl bromide inN,N-dimethylformamide, and the mixture was stirred at 20° C. for 3hours. The reaction mixture was extracted with ethyl acetate and withwater. The organic layer was washed with water and with a sodiumchloride aqueous solution, and was then dried over magnesium sulfate.The solvent was distilled off under reduced pressure to give 330 mg ofyellow oil of ethyl 3-[N-(2-cyanobenzyl)butyrylamino]-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 0.86 (3H, t, J=8 Hz), 1.49 (3H, t, J=8 Hz), 1.67(2H, sextet, J=8 Hz), 2.02 (2H, t, J=8 Hz), 4.28-4.52 (2H, m), 4.90 (1H,d, J=15 Hz), 5.28 (1H, d, J=15 Hz), 7.40 (1H, t, J=8 Hz), 7.61 (1H, dt,J=1, 8 Hz), 7.70 (1H, d, J=1 Hz), 7.74 (1H, dd, J=1, 8 Hz), 8.02 (1H, d,J=10 Hz), 8.22 (1H, dd, J=1, 10 Hz).

PRODUCTION EXAMPLE 6

The following compounds were produced in the same manner as inProduction Example 5.

PRODUCTION EXAMPLE 6-1 Ethyl3-[N-(3-fluorobenzyl)butyrylamino]-4-nitrobenzoate

Properties of the compound:

yellow oil.

¹ H-NMR (CDCl₃, δ): 0.86 (3H, t, J=7.5 Hz), 1.35 (3H, t, J=7.5 Hz), 1.68(2H, m), 2.00 (2H, t, J=7.5 Hz), 4.36 (1H, d, J=15 Hz), 4.40 (2H, m),5.31 (1H, d, J=15 Hz), 6.85-7.28 (4H, m), 7.60 (1H, d, J=1.5 Hz), 7.97(1H, d, J=10 Hz), 8.16 (1H, dd, J=10,1.5 Hz).

PRODUCTION EXAMPLE 6-2 Ethyl4-nitro-3-[N-(2-pyridylmethyl)-n-butyrylamino]benzoate

This compound was used in the subsequent step at once.

Property of the compound:

yellow oil.

PRODUCTION EXAMPLE 6-3 Ethyl3-[N-(2,6-dichlorobenzyl)butyrylamino]-4-nitrobenzoate

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 0.89 (3H, t, J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz), 1.70(2H, m), 2.03 (2H, t, J=7.5 Hz), 4.36 (2H, m), 4.96 (1H, d, J=13.5 Hz),5.70(1H, d, J=13.5 Hz), 7.10-7.28 (3H, m), 7.49 (1H, d, J=1.5 Hz), 8.03(1H, d, J=7.5 Hz), 8.14 (1H, dd, J=7.5 and 1.5 Hz).

mp: 85-89° C.

PRODUCTION EXAMPLE 6-4 Ethyl3-[N-(3-methylbenzyl)propionylamino]-4-nitrobenzoate

This compound was used in the subsequent step at once.

Property of the compound:

yellow oil.

PRODUCTION EXAMPLE 6-5 Ethyl3-[N-(2-fluorobenzyl)cyclopropanecarbonylamino]-4-nitrobenzoate

Properties of the compound:

yellow oil.

¹ H-NMR (CDCl₃, δ): 0.60-0.71 (2H, m), 0.99-1.14 (3H, m), 1.38 (3H, t,J=7.5 Hz), 4.37 (2H, m), 4.62 (1H, d, J=12 Hz), 5.30 (1H, d, J=12 Hz),6.92 (1H, t, J=7.5 Hz), 7.10 (1H, t, J=7.5 Hz), 7.26 (1H, m), 7.42 (1H,t, J=7.5 Hz), 7.80 (1H, s), 7.99 (1H, d, J=7.5 Hz), 8.14 (1H, dd, J=7.5and 2 Hz).

PRODUCTION EXAMPLE 6-6 Ethyl3-[N-(2-chlorobenzyl)cyclobutanecarbonylamino]-4-nitrobenzoate

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 1.37 (3H, t, J=7.5 Hz), 1.68-1.87 (4H, m), 2.22-2.58(2H, m), 2.75-2.94 (1H, m), 4.23-4.46 (2H, m), 4.63 (1H, d, J=15 Hz),5.45 (1H, d, J=15 Hz), 7.14-7.24 (3H, m), 7.35-7.45 (1H, m), 7.56 (1H,d, J=2 Hz), 7.97 (1H, d, J=9 Hz), 8.13 (1H, dd, J=9, 2 Hz).

PRODUCTION EXAMPLE 6-7 Ethyl 3-cyclobutanecarbonylamino-4-nitrobenzoate

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 1.43 (3H, t, J=7.5 Hz), 1.86-2.19 (2H, m), 2.22-2.54(4H, m), 3.20-3.41 (1H, m), 4.43 (2H, q, J=7.5 Hz), 7.80 (1H, dd, J=10,2 Hz), 8.26 (1H, d, J=10 Hz), 9.45 (1H, d, J=2 Hz).

mp: 94-96° C.

PRODUCTION EXAMPLE 7 Production of 3-acetylamino-4-nitrobenzamide

Oxalyl chloride (3.91 ml) was added dropwise to a solution of 7.00 g of3-acetylamino-4-nitrobenzoic acid in 50 ml of dichloromethane in anitrogen atmosphere while being cooled with ice, and the mixture wasstirred for 1 hour while being cooled with ice and then at roomtemperature for 2.5 hours. The reaction solvent was distilled off underreduced pressure, and the residue was then dissolved in 50 ml oftetrahydrofuran. The solution was added dropwise to 28% aqueous ammoniain a nitrogen atmosphere while being cooled with ice. The reactionsolution was stirred for 1 hour, and water and ethyl acetate were addedthereto. Approximately 8 g of the solid material precipitated werecollected through filtration. After the filtrate was separated, theorganic layer was washed with water, and dried over magnesium sulfate.Then, the solvent was distilled off under reduced pressure to obtain theresidue. The solid material precipitated and the residue were combined,washed with hot ethyl acetate, and collected through filtration to give4.94 g of 3-acetylamino-4-nitrobenzamide.

Properties of the compound:

¹ H-NMR (DMSO-d6, δ): 2.08 (3H, s), 7.68 (1H, br s), 7.78 (1H, dd, J=9,2 Hz), 7.94-8.05 (2H, m), 8.23 (1H, brs).

Mass (FAB): 224.

PRODUCTION EXAMPLE 8 Production of3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide

3- [N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide was produced fromthe compound in the same manner as in Production Example 7.

Properties of the compound:

¹ H-NMR (DMSO-d6, δ): 1.86 (3H, s), 4.64 (1H, d, J=l5 Hz), 5.06 (1H, d,J=15 Hz), 7.22-7.40 (4H, m), 7.73 (1H, br s), 7.84 (1H, d, J=2 Hz), 8.03(1H, dd, J=9, 2 Hz), 8.14 (1H, d, J=9 Hz), 8.22 (1H, br s).

PRODUCTION EXAMPLE 9 Production of3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenznitrile

Thirty milliliters of 1,4-dioxane were added dropwise to a solution of1.70 ml of titanium tetrachloride in 4 ml of dichloromethane in anitrogen atmosphere while being cooled with ice. Then, a solution of2.70 g of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide in 65 ml of1,4-dioxane was added dropwise thereto. After the mixture was stirredfor 15 minutes, 3.14 g of triethylamine were added thereto, and themixture was stirred for 2 hours while being cooled with ice. After thecompletion of the reaction, the solvent was distilled off under reducedpressure, and the residue was extracted with ethyl acetate and withwater. The organic layer was washed with water, and was dried overmagnesium sulfate. Subsequently, the solvent was distilled off underreduced pressure. The residue was purified through column chromatography(200 ml, a mixture of n-hexane and ethyl acetate at a ratio of 4:1] togive 1.21 g of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenznitrile.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 1.92 (3H, s), 4.61 (1H, d, J=15 Hz), 5.40 (1H, d,J=15 Hz), 7.18-7.50 (5H, m), 7.80 (1H, dd, J=9, 2 Hz), 8.01 (1H, d, J=9Hz) Mass (FAB): 300.

IR (Nujol): 2250 cm⁻¹.

PRODUCTION EXAMPLE 10 Production of3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile

One milliliter of 35% hydrochloric acid was added to a solution of 850mg of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide in 10 ml of1,4-dioxane, and the mixture was heat-refluxed for 4 days. After thesolvent was distilled off from the reaction solution under reducedpressure, the residue was separated by being poured in a mixturesolution of water and chloroform. The organic layer was washed withwater, and was dried over magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified through columnchromatography [50 ml, chloroform] to give 230 mg of3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile.

Properties of the compound:

¹ H-NMR (CDCl₃, δ): 4.65 (2H, d, J=6 Hz), 6.93 (1H, dd, J=9, 2 Hz), 7.10(1H, d, J=2 Hz), 7.25-7.40 (3H, m), 7.40-7.54 (1H, m), 8.30 (1H, d, J=9Hz), 8.45 (1H, br s).

Mass (FAB): 258.

IR (Nujol): 2220 cm⁻¹.

PRODUCTION EXAMPLE 11 Production of4-amino-3-[N-(2-chlorobenzyl)amino]-benznitrile

Fifty milligrams of 10% palladium on carbon were added to a mixedsolution of 261 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile, 15ml of methanol and 3 ml of 1,4-dioxane to conduct the catalyticreduction in a hydrogen atmosphere at 3 atm. After the completion of thereaction, the reaction solution was filtered through celite, and thefiltrate was distilled off under reduced pressure. The resulting solidmaterial was washed with ether, and was collected through filtration togive 196 mg of 4-amino-3-[N-(2-chlorobenzyl)amino]benznitrile.

Properties of the compound:

¹ H-NMR (DMSO-d6, δ): 4.39 (2H, d, J=5 Hz), 5.57 (1H, t, J=5 Hz), 5.69(2H, s), 6.46 (1H, d, J=2 Hz), 6.61 (1H, d, J=9 Hz), 6.88 (1H, dd, J=9,2 Hz), 7.25-7.41 (3H, m), 7.44-7.54 (1H, m).

EXAMPLE 1 Synthesis of1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (42)

A suspension obtained by adding 390 mg of ethyl3-[N-(2-bromobenzyl)butyrylamino]-4-nitrobenzoate and 210 mg of reducediron to a mixed solution of 1 ml of acetic acid and 2 ml of ethanol wasrefluxed for 1 hour while being vigorously stirred. After the completionof the reaction, the reaction solution was cooled down and filteredthrough celite, and the filtrate was then concentrated under reducedpressure. The residue was separated with the addition of ethyl acetateand a sodium hydrogencarbonate aqueous solution. After the organicsolvent layer was dried, the solvent was distilled off under reducedpressure, and the brown residue was obtained. This residue was purifiedthrough flash column chromatography to give 160 mg of yellow crystals of1-(2-bromobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (42).

Properties of Compound (42):

¹ H-NMR (CDCl₃, δ): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t, J=8 Hz),1.78-1.98 (2H, m), 2.34 (2H, t, J=8 Hz), 4.38 (2H, q, J=8 Hz), 5.45 (2H,s), 6.65 (1H, t, J=8 Hz), 7.00 (1H, t, J=8 Hz), 7.13 (1H, t, J=8 Hz),7.28 (1H, t, J=8 Hz), 7.78 (1H, d, J=10 Hz), 7.99 (1H, d, J=10 Hz), 8.02(1H, s).

mp: 134-135° C.

EXAMPLE 2 Synthesis of1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (43)

In the same manner as in Example 1, 160 mg of colorless crystals of1-(2-cyanobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (43) wereformed from 390 mg of ethyl3-[N-(2-cyanobenzyl)butyrylamino]-4-nitrobenzoate.

Properties of Compound (43):

¹ H-NMR (CDCl₃, δ): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t, J=8 Hz), 1.88(2H, sextet, J=8 Hz), 2.80 (2H, t, J=8 Hz), 4.38 (2H, q, J=8 Hz), 5.62(2H, s), 6.57-6.63 (1H, m), 7.38-7.50 (2H, m), 7.78 (1H, dd, J=1, 8 Hz),7.79 (1H, d, J=8 Hz), 7.94 (1H, d, J=1 Hz), 8.03 (1H, dd, J=1, 8 Hz).

mp: 132-134° C.

EXAMPLE 3 Synthesis of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenylbenzimidazole (44)

In the same manner as in Example 1, 220 mg of yellow crystals of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-phenylbenzimidazole (44) wereobtained from 460 mg of ethyl3-[N-(2-chlorobenzyl)benzoylamino]-4-nitrobenzoate.

Properties of Compound (44):

¹ H-NMR (CDCl₃, δ): 1.40 (3H, t, J=8 Hz), 4.38 (2H, q, J=8 Hz), 5.56(2H, s), 6.72 (H, dd, J=1, 8 Hz), 7.18 (1H, dt, J=1, 8 Hz), 7.30 (1H,dt, J=1, 8 Hz), 7.45-7.55 (4H, m), 7.64 (1H, d, J=1Hz), 7.68 (1H, d, J=1Hz), 7.90 (1H, d, J=10 Hz), 7.95 (1H, s), 8.08 (1H, dd, J=1, 8 Hz).

mp: 140-142° C.

EXAMPLE 4 Synthesis of6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propylbenzimidazole (45)

In the same manner as in Example 1, 160 mg of colorless crystals of6-ethoxycarbonyl-1-(2-fluorobenzyl)-2-n-propylbenzimidazole (45) wereformed from 390 mg of ethyl3-[N-(2-fluorobenzyl)butyrylamino]-4-nitrobenzoate.

Properties of Compound (45):

¹ H-NMR (CDCl₃, δ): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t, J=8 Hz),1.78-1.98 (2H, m), 2.34 (2H, t, J=8 Hz), 4.38 (2H, q, J=8 Hz), 5.45 (2H,s), 6.65 (1H, t, J=8 Hz), 7.00 1H, t, J=8 Hz), 7.13 (1H, t, J=8 Hz),7.28 (1H, t, J=8 Hz), 7.78 (1H, d, J=10 Hz), 7.99 (1H, d, J=10 Hz), 8.02(1H, s).

mp: 134-135° C.

EXAMPLE 5 Synthesis of6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propylbenzimidazole (46)

In the same manner as in Example 1, 160 mg of colorless crystals of6-ethoxycarbonyl-1-(4-fluorobenzyl)-2-n-propylbenzimidazole (46) wereformed from 400 mg of ethyl3-[N-(4-fluorobenzyl)butyryl)amino]-4-nitrobenzoate.

Properties of Compound (46):

¹ H-NMR (CDCl₃, δ): 1.04 (3H, t, J=8 Hz), 1.40 (3H, t, J=8 Hz), 1.88(2H, sextet, J=8 Hz), 2.82 (2H, t, J=8 Hz), 4.38 (2H, q, J=8 Hz), 5.38(2H, s), 7.00 (4H, d, J=7 Hz), 7.77 (1H, d, J=8 Hz), 7.98 (1H, d, J=1Hz), 8.00 (1H, dd, J=1, 8 Hz).

mp: 134-135° C.

EXAMPLE 6

The following compounds were formed in the same manner as in Example 1.

EXAMPLE 6-1 6-Ethoxycarbonyl-2-n-propyl-1-(2-pyridylmethyl)benzimidazole(47)

Properties of Compound (47)

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=7.5 Hz), 1.39 (3H, t, J=7.5 Hz), 1.89(2H, m), 2.86 (2H, t, J=7.5 Hz), 4.38 (2H, q, J=7.5 Hz), 5.50 (2H, s),6.72 (1H, d, J=7.5 Hz), 7.24 (1H, m), 7.58 (1H, dt, J=7.5,1.5 Hz), 7.79(1H, d, J=7.5 Hz), 7.96-8.02 (2H, m), 8.60 (1H, d, J=4 Hz).

mp: 84-85° C.

EXAMPLE 6-2 6-Ethoxycarbonyl-1-(3-fluorobenzyl)-2-n-propylbenzimidazole(48)

Properties of Compound (48)

¹ H-NMR (CDCl₃, δ): 1.04 (3H, t, J=7.5 Hz), 1.39 (3H, t, J=7.5 Hz), 1.90(2H, m), 2.81 (2H, t, J=7.5 Hz), 4.39 (2H, q, J=7.5 Hz), 5.39 (2H, s),6.70-6.84 (2H, m), 7.00 (1H, dt, J=8.5 and 1.5 Hz), 7.78 (1H, d, J=8.5Hz), 7.96 (1H, s), 8.00 (1H, d, J=8.5 Hz).

mp: 142-146° C.

EXAMPLE 6-31-(2,6-Dichlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (49)

Properties of Compound (49)

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=7.5 Hz), 1.38 (3H, t, J=7.5 Hz), 1.88(2H, m), 2.93 (2H, t, J=7.5 Hz), 4.34 (2H, q, J=7.5 Hz), 5.61 (2H, s),7.26 (1H, d, J=7.5 Hz), 7.39 (2H, d, J=7.5 Hz), 7.68 (1H, d, J=7.5 Hz),7.84 (1H, d, J=1.5 Hz), 7.91 (2H, d, J=7.5 Hz).

mp: 153-156° C.

EXAMPLE 6-4 1-(3-Methylbenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole(50)

Properties of Compound (50):

colorless solid.

¹ H-NMR (CDCl₃, δ): 1.02 (3H, t, J=7.5 Hz), 1.41 (3H, t, J=7.5 Hz), 1.89(2H, m), 2.29 (3H, s), 2.82 (2H, t, J=7.5 Hz), 4.38 (2H, q, J=7.5 Hz),5.35 (2H, s), 6.79-6.86 (2H, m), 7.09 (1H, d, J=7.5 Hz), 7.20 (1H, t,J=7.5 Hz), 7.76 (1H, d, J=7.5 Hz), 7.95-8.02 (2H, m).

EXAMPLE 6-52-Cyclopropyl-6-ethoxycarbonyl-1-(2-fluorobenzyl)benzimidazole (51)

Properties of Compound (51):

¹ H-NMR (CDCl₃, δ): 1.10 (2H, m), 1.27 (2H, m), 1.40 (3H, t, J=7.5 Hz),1.95 (1H, m), 4.37 (2H, q, J=7.5 Hz), 5.56 (2H, s), 6.77 (1H, t, J=7.5Hz), 7.03 (1H, t, J=7.5 Hz), 7.13 (1H, t, J=7.5 Hz), 7.29 (1H, m), 7.69(1H, d, J=7.5 Hz), 7.96 (1H, d, J=7.5 Hz), 8.02 (1H, d, J=2 Hz).

mp: 122-126° C.

EXAMPLE 6-6 1-(2-Chlorobenzyl)-6-cyano-2-cyclopropylbenzimidazole (52)

Properties of Compound (52):

¹ H-NMR (CDCl₃, δ): 1.04-1.24 (2H, m), 1.24-1.39 (2H, m), 1.83-2.01 (1H,m), 5.58 (2H, s), 6.54 (1H, d, J=9 Hz), 7.16 (1H, td, J=9, 2 Hz),7.22-7.38 (1H, m), 7.43-7.56 (3H, m), 7.74 (1H, dd, J=9, 2 Hz).

Mass (FAB): 308 (M+1).

IR (Nujol): 2210 cm⁻¹.

EXAMPLE 6-71-(2-Chlorobenzyl)-2-cyclobutyl-6-ethoxycarbonylbenzimidazole (53)

Properties of Compound (53):

¹ H-NMR (CDCl₃, δ): 1.38 (3H, t, J=7.5 Hz), 1.90-2.21 (2H, m), 2.21-2.24(2H, m), 2.46-2.70 (2H, m), 3.52-3.73 (1H, m), 4.37 (2H, q, J=7.5 Hz),5.39 (2H, s), 6.34 (1H, dd, J=9, 2 Hz), 7.06 (1H, td, J=9, 2 Hz), 7.23(1H, td, J=9, 2 Hz), 7.46 (1H, dd, J=9, 2 Hz), 7.83 (1H, d, J=9 Hz),7.92 (1H, d, J=2 Hz), 8.01 (1H, dd, J=9, 2 Hz).

mp: 111-113° C.

EXAMPLE 6-8 1-(2-Chlorobenzyl)-6-ethoxycarbonyl-2-n-pentylbenzimidazole(54)

Properties of Compound (54):

¹ H-NMR (CDCl₃, δ): 0.87 (3H, t, J=7.5 Hz), 1.22-1.47 (7H, m), 1.74-1.93(2H, m), 2.80 (2H, t, J=7.5 Hz), 4.37 (2H, q, J=7.5 Hz), 5.47 (2H, s),6.39 (1H, dd, J=9, 2 Hz), 7.08 (1H, td, J=9, 2 Hz), 7.19-7.33 (1H, m),7.48 (1H, dd, J=9, 2 Hz), 7.79 (1H, d, J=9 Hz), 7.94 (1H, d, J=2 Hz),8.00 (1H,dd, J=9, 2 Hz).

EXAMPLE 7 5-Carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (55)

Twenty milliliters of ethanol and 10.4 g of a 10% sodium hydroxideaqueous solution were added to 2.8 g of1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-n-propylbenzimidazole, and themixture was heat-refluxed for 4 hours. The reaction solution was cooled,and was then adjusted to a pH of 6 with 10% hydrochloric acid. Thecrystals were collected, washed with water, and dried under reducedpressure to give 2.46 g of a colorless solid of5-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (55).

Properties of Compound (55):

¹ H-NMR (DMSO-d6, δ): 0.93 (3H, t, J=7.5 Hz), 1.75 (2H, m), 2.79 (2H,t,J=7.5 Hz), 5.61 (2H, s), 6.49 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.5Hz),7.33 (1H, t, J=7.5 Hz), 7.46 (1H, d, J=7.5 Hz), 7.56 (1H, d, J=7.5Hz), 7.80 (1H, d, J=7.5 Hz), 8.20 (1H, s).

EXAMPLE 8

The following compounds were formed in the same manner as in Example 7.

EXAMPLE 8-1 6-Carboxy-1-(3-methylbenzyl)-2-n-propylbenzimidazole (56)

Properties of Compound (56):

colorless solid.

¹ H-NMR (DMSO-d6, δ): 0.97 (3H, t, J=7.5 Hz), 1.78 (2H, m), 2.23 (3H,s), 3.86 (2H, q, J=7.5 Hz), 5.53 (2H, s), 6.80 (1H, d, J=7.5 Hz), 6.91(1H,s), 7.07 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.65 (1H, d,J=7.5 Hz), 7.79 (1H, d, J=7.5 Hz), 8.04 (1H, s).

EXAMPLE 8-2 2-n-Butyl-7-carboxy-1-(2-chlorobenzyl)benzimidazole (57)

Properties of Compound (57):

¹ H-NMR (DMSO-d6, δ): 0.84 (3H, t, J=7.5 Hz), 1.34 (2H, m), 1.71 (2H,m), 2.80 (2H, t, J=7.5 Hz), 5.89 (2H, s), 6.03 (1H, d, J=7.5 Hz), 7.13(1H, t, J=7.5 Hz), 7.27 (2H, t, J=7.5 Hz), 7.48 (1H, d, J=7.5 Hz), 7.63(1H, d, J=7.5 Hz), 7.87 (1H, d, J=7.5 Hz).

EXAMPLE 8-3 6-Carboxy-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole (58)

Properties of Compound (58):

¹ H-NMR (DMSO-d6, δ): 1.04-1.19 (4H, m), 2.37 (1H, m), 5.79 (2H, s),7.00 (1H, t, J=7.5 Hz), 7.15 (1H, t, J=7.5 Hz), 7.27 (1H, t, J=10.5 Hz),7.37 (1H, m), 7.60 (1H, d, J=7.5 Hz), 7.82 (1H, d, J=7.5 Hz), 8.11 (1H,s).

mp: 224-229° C.

EXAMPLE 8-4 2-n-Butyl-6-carboxy-1-(2-fluorobenzyl)benzimidazole (59)

Properties of Compound (59):

¹ H-NMR (DMSO-d6, δ): 0.87 (3H, t, J=7.5 Hz), 1.26-1.48 (2H, m),1.60-1.80 (2H, m), 2.90 (2H, t, J=7.5 Hz), 5.63 (2H, s), 6.89 (1H, td,J=9, 2 Hz), 7.13 (1H, td, J=9, 2 Hz), 7.20-7.44 (2H, m), 7.64 (1H, d,J=9 Hz), 7.80 (1H, dd, J=9, 2 Hz), 8.08 (1H, d, J=2 Hz).

mp: 216-219° C.

EXAMPLE 9 Synthesis of1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazolehydrochloride (60)

Oxalyl chloride (0.208 ml) was added dropwise to a suspension preparedby adding 390 mg of6-carboxy-1-(2-chlorobenzyl)-2-cyclopropylbenzimidazole to 10 ml ofmethylene chloride containing 1 drop of N,N-dimethylformamide at roomtemperature over a period of several minutes. The mixture was stirred atthe same temperature for 2 hours, and was then concentrated underreduced pressure. Isopropyl ether was added to the residue, and themixture was pulverized to give 450 mg of1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazolehydrochloride (60) as a white powder. Since this product was unstable,it was used as a starting material in the subsequent step without beingpurified.

EXAMPLE 10 Synthesis of1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole(61)

Four-hundred milligrams of6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole were dissolved in 3ml of methylene chloride containing 1 drop of N,N-dimethylformamide.Oxalyl chloride (28 mg) was added to this solution at 5° C. Thethus-obtained solution was stirred at room temperature for 1 hour, andwas then concentrated under reduced pressure. The residue was dissolvedin 3 ml of methylene chloride, and the mixture was added to a mixedsolution prepared by adding 271 mg of 4-dimethylaminobenzylaminehydrochloride and 1 ml of triethylamine to 10 ml of methylene chlorideat room temperature. The resulting reaction mixture was stirred at thesame temperature for 1 hour, washed with water, dried and thenconcentrated under reduced pressure. The residue was developed andpurified through thin-layer chromatography to give 215 mg of1-(2-chlorobenzyl)-6-(4-dimethylaminophenylmethylcarbamoyl)-2-n-propylbenzimidazole(61).

Properties of Compound (61):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.01 (3H, t, J=7 Hz), 1.88 (2H, sextet, J=7 Hz),2.76 (2H, t, J=7 Hz), 2.95 (6H, s), 4.50 (2H, d, J=5 Hz), 5.45 (2H, s),6.32 (1H, d, J=5 Hz), 6.36 (1H, d, J=7 Hz), 6.72 (2H, d, J=10 Hz), 7.07(1H, dt, J=1, 8 Hz), 7.20-7.25 (3H, m), 7.46 (1H, dd, J=1, 8 Hz), 7.58(1H, dd, J=1, 8 Hz), 7.76 (1H, d, J=8 Hz), 7.82 (1H, d, J=1Hz).

mp: 155-156° C.

EXAMPLE 11 Synthesis of1-(2-chlorobenzyl)-6-morpholino-carbamoyl-2-n-propylbenzimidazole (62)

In the same manner as in Example 10, 205 mg of1-(2-chlorobenzyl)-6-morpholinocarbamoyl-2-n-propylbenzimidazole (62)were formed from 200 mg of6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 124 mg of4-aminomorpholine.

Properties of Compound (62):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=8 Hz), 1.88 (2H, sextet, J=8 Hz),2.62 (4H, bs), 2.72 (2H, t, J=8 Hz), 3.85 (4H, bs), 5.42 (2H, s), 6.42(1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 7.20-7.28 (3H, m), 7.47(1H, dd, J=1, 8 Hz), 7.78 (1H, dd, J=1, 8 Hz).

mp: 195-197° C.

EXAMPLE 12 Synthesis of1-(2-chlorobenzyl)-2-n-propyl-6-thiomorpholinocarbonylbenzimidazole (63)

In the same manner as in Example 10, 160 mg of1-(2-chlorobenzyl-2-n-propyl-6-thiomorpholinocarbonyl-benzimidazole (63)were formed from 200 mg of6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 125 mg ofthiomorpholine.

Properties of Compound (63):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=8 Hz), 1.88 (2H, sextet, J=8 Hz),2.78 (2H, t, J=8 Hz), 2.96 (4H, bt, J=5 Hz), 3.88 (4H, bt, J=5 Hz), 5.46(2H, s), 6.34 (1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 7.26 (2H,dt, J=1, 8 Hz), 7.47 (1H, dd, J=1, 8 Hz), 7.58 (1H, bd, J=8 Hz), 7.76(1H, s), 7.78 (1H, d, J=8 Hz).

mp: 160-162° C.

EXAMPLE 13 Synthesis of2-n-butyl-1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(64)

In the same manner as in Example 10, 230 mg of2-n-butyl-1-(2-chlorobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(64) were formed from 200 mg of6-carboxy-2-n-butyl-1-(2-chlorobenzyl)-benzimidazole and 126 mg of2-aminomethylpyridine.

Properties of Compound (64):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 0.92 (3H, t, J=8 Hz), 1.42 (2H, sextet, J=8 Hz),1.82 (2H, quintet, J=8 Hz), 2.82 (2H, t, J=8 Hz), 4.76 (1H, d, J=5 Hz),5.46 (2H, s), 6.38 (1H, dd, J=1, 8 Hz), 7.08 (1H, dt, J=1, 8 Hz),7.18-7.26 (2H, m), 7.32 (1H, d, J=8 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.62(1H, dt, J=1, 8 Hz), 7.72 (1H, dt, J=1, 8 Hz), 7.82 (1H, d, J=8 Hz),7.88 (1H, d, J=1Hz), 8.56 (1H, dd, J=1, 8 Hz).

mp: 175-176° C.

EXAMPLE 14 Synthesis of2-n-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole (65)

In the same manner as in Example 10, 170 mg of2-n-butyl-5-carbamoyl-1-(2-chlorobenzyl)benzimidazole (65) were formedfrom 100 mg of 2-n-butyl-1-(2-chlorobenzyl)-5-carboxybenzimidazole.

Properties of Compound (65):

colorless crystal.

¹ H-NMR (DMSO-d6, δ): 0.84 (3H, t, J=8 Hz), 1.35 (2H, sextet, J=8 Hz),1.68 (2H, quintet, J=8 Hz), 2.78 (2H, t, J=8 Hz), 5.58 (2H, s), 6.50(1H, dd, J=1, 8 Hz), 7.25 (1H, dt, J=1, 8 Hz), 7.28 (1H, bs), 7.35 (1H,dt, J=1, 8 Hz), 7.42 (1H, d, J=10 Hz), 7.56 (1H, dd, J=1, 8 Hz), 7.74(1H, dd, J=1, 10 Hz), 7.96 (1H, bs), 8.20 (1H, d, J=1Hz).

mp: 195-198° C.

EXAMPLE 15 Synthesis of1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole (66)

1-(2-Chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazolehydrochloride (140 mg) was added to a solution prepared by adding 298 mgof morpholine (30% methanol solution) to 10 ml of methylene chloride atroom temperature. The reaction mixture was stirred at the sametemperature for 1 hour, then washed with water, dried, and concentratedunder reduced pressure. The residue was recrystallized with ether togive 20 mg of1-(2-chlorobenzyl)-2-cyclopropyl-6-morpholinocarbonylbenzimidazole (66).

Properties of Compound (66):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.04-1.12 (2H, m), 1.25-1.32 (2H, m), 1.82-1.96 (1H,m), 3.68 (8H, bs), 5.56 (2H, s), 6.55 (1H, dd, J=1, 8 Hz), 7.13 (1H, dt,J=1, 8 Hz), 7.22-7.29 (2H, m), 7.30 (1H, d, J=1Hz), 7.46 (1H, dd, J=1, 8Hz), 7.77 (1H, d, J=8 Hz).

mp: 193-195° C.

EXAMPLE 16 Synthesis of1-(2-chlorobenzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(67)

In the same manner as in Example 15, 95 mg of1-(2-chlorobenzyl)-2-cyclopropyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(67) were formed from 150 mg of1-(2-chlorobenzyl)-6-chlorocarbonyl-2-cyclopropylbenzimidazolehydrochloride and 85 mg of 2-aminomethylpyridine.

Properties of Compound (67):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.02-1.13 (2H, m), 1.24-1.32 (2H, m), 1.82-1.95 (1H,m), 4.76 (2H, d, J=5 Hz), 5.59 (2H, s), 7.11 (1H, dt, J=1, 8 Hz),7.20-7.26 (2H, m), 7.34 (1H, d, J=8 Hz), 7.46 (1H, dd, J=1, 8 Hz), 7.60(1H, t, J=5 Hz), 7.66 (1H, dd, J=1, 8 Hz), 7.73 (1H, s), 7.88 (1H, s).

mp: 134-135° C.

EXAMPLE 17

The following compounds were formed in the same manner as in Example 15.

EXAMPLE 17-11-(2-Chlorobenzyl)-2-cyclopropyl-6-(2-pyridylcarbamoyl)benzimidazole(68)

Properties of Compound (68):

¹ H-NMR (CDCl₃, δ): 1.16 (2H, m), 1.32 (2H, m), 1.92 (1H, m), 5.61 (2H,s), 6.57 (1H, d, J=7.5 and 1.5 Hz), 7.15 (1H, dt, J=7.5 and 1.5 Hz),7.22-7.31 (2H, m), 7.48 (1H, dd, J=7.5 and 1.5 Hz), 7.77 (1H, d, J=9Hz), 8.05 (2H, m).

mp: 206-209° C.

EXAMPLE 17-26-(2-Carboxy-1-pyrrolidinocarbonyl)-1-(2-chlorobenzyl)-2-n-propylbenzimidazole(69)

Properties of Compound (69):

¹ H-NMR (DMSO-d6, δ): 0.92 (3H, t, J=7.5 Hz), 1.65-1.99 (5H, m), 2.25(1H, m), 2.77 (2H, t, J=7.5 Hz), 3.50 (2H, m), 4.40 (1H, m), 5.52 (2H,s), 6.53 (1H, d, J=7.5 Hz), 7.21-7.71 (6H, m).

mp: 96° C.

EXAMPLE 17-31-(2-Chlorobenzyl)-2-cyclobutyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(70)

Properties of Compound (70):

¹ H -NMR (CDCl₃, δ): 1.90-2.21 (2H, m), 2.25-2.37 (2H, m), 2.40-2.65(2H, m), 3.64 (1H, m), 4.76 (2H, d, J=5 Hz), 5.39 (2H, s), 6.33 (1H, d,J=7.5 Hz), 7.05 (1H, t, J=7.5 Hz), 7.16-7.26 (2H, m), 7.33 (1H, d, J=7.5Hz), 7.46 (1H, d, J=7.5 Hz), 7.69-7.76 (3H, m), 7.73 (1H, d, J=7.5 Hz),7.86 (1H, s), 8.55 (1H, d, J=5 Hz).

mp: 183-185° C.

EXAMPLE 17-4(1-(2-Chlorobenzyl)-2-n-propyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(71)

Properties of Compound (71)

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=7.5 Hz), 1.90 (2H, m), 2.80 (2H, t,J=7.5 Hz), 4.80 (2H, d, J=5 Hz), 5.44 (2H, s), 6.40 (1H, d, J=7.5 Hz),7.09 (1H, t, J=7.5 Hz), 7.21-7.27 (3H, m), 7.34 (1H, d, J=7.5 Hz), 7.47(1H, d, J=7.5 Hz), 7.64-7.72 (2H, m), 7.83 (1H, dd, J=7.5 and 2 Hz),8.30 (1H, d, J=2 Hz), 8.56 (1H, d, J=5 Hz).

mp: 115-116° C.

EXAMPLE 17-51-(2-Chlorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]-2-n-propylbenzimidazole(72)

Properties of Compound (72):

¹ H -NMR (DMSO-d6, δ): 1.03 (3H, t, J=7.5 Hz), 1.87 (2H, m), 2.79 (2H,t, J=7.5 Hz), 3.05 (3H, brs), 4.60 (1H, brs), 4.87 (1H, brs), 5.40 (2H,d, J=unknown), 6.38 (1H, d, J=unknown), 7.05 (1H, brs), 7.20 (3H, m),7.35-7.49 (3H, m), 7.60-7.81 (2H, m), 8.54 (1H, brs).

mp: 99° C.

EXAMPLE 17-61-(2-Chlorobenzyl)-6-piperonylcarbamoyl-2-n-propylbenzimidazole (73)

Properties of Compound (73):

¹ H -NMR (CDCl₃, δ): 1.01 (3H, t, J=7.5 Hz), 1.88 (2H, m), 2.78 (2H, t,J=7.5 Hz), 4.54 (2H, d, J=5 Hz), 5.45 (2H, s), 5.95 (2H, s), 6.36 (1H,d, J=7.5 Hz), 6.44 (1H, t, J=5 Hz), 6.75-6.85 (3H, m), 7.08 (1H, t,J=7.5 Hz), 7.23 (1H, t, J=7.5 Hz), 7.45 (1H, d, J=7.5 Hz), 7.67 (1H, dd,J=7.5, 2 Hz), 7.78 (1H, d, J=7.5 Hz), 7.83 (1H, s).

mp: 131-134° C.

EXAMPLE 17-71-(2-chlorobenzyl)-6-phenylcarbamoyl-2-n-propylbenzimidazole (74)

Properties of Compound (74):

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=7.5 Hz), 1.90 (2H, m), 2.81 (2H, t,J=7.5 Hz), 5.47 (2H, s), 6.40 (1H, d, J=7.5 Hz), 7.06-7.18 (2H, m), 7.26(1H, t, J=7.5 Hz), 7.35 (2H, t, J=7.5 Hz), 7.48 (1H, d, J=7.5 Hz), 7.64(2H, d, J=7.5 Hz), 7.72 (1H, dd, J=7.5 and 2 Hz), 7.85-7.95 (3H, m).

mp: 168° C.

EXAMPLE 17-81-(2-Chlorobenzyl)-2-n-propyl-6-[(4-pyridylmethyl)carbamoyl]benzimidazole(75)

Properties of Compound (75):

¹ H-NMR (DMSO-d6, δ): 0.93 (3H, t, J=7.5 Hz), 1.76 (2H, m), 2.78 (2H, t,J=7.5 Hz), 4.49 (2H, d, J=5 Hz), 6.42 (1H, d, J=7.5 Hz), 7.22 (1H, t,J=7.5 Hz), 7.27 (2H, d, J=7.5 Hz), 7.34 (1H, t, J=7.5 Hz), 7.57 (1H, d,J=7.5 Hz), 7.69 (1H, d, J=7.5 Hz), 7.80 (1H, d, J=7.5 Hz), 7.97 (1H, s),8.48 (2H, d, J=7.5 Hz), 9.03 (1H, t, J=5 Hz).

mp: 170-173° C.

EXAMPLE 17-91-(2-Chlorobenzyl)-2-n-propyl-6-[(3-pyridylmethyl)carbamoyl]benzimidazole(76)

Properties of Compound (76):

¹ H-NMR (DMSO-d6, δ): 0.95 (3H, t, J=7.5 Hz), 1.76 (2H, m), 2.80 (2H, t,J=7.5 Hz), 4.50 (2H, d, J=5 Hz), 5.60 (2H, s), 6.42 (1H, d, J=7.5 Hz),7.23 (1H, t, J=7.5 Hz), 7.30-7.58 (2H, m), 7.57 (1H, d, J=7.5 Hz),7.67-7.74 (2H, m), 7.75 (1H, d, J=7.5 Hz), 7.97 (1H, s), 8.46 (1H, d,J=5 Hz), 8.56 (1H, s), 9.0 (1H, t, J=5 Hz).

mp: 193-195° C.

EXAMPLE 17-101-(2-Chlorobenzyl)-6-[N-methyl-N-(2-pyridyl)carbamoyl]-2-n-propylbenzimidazole(77)

Properties of Compound (77):

¹ H-NMR (DMSO-d6, δ): 0.90 (3H, t, J=7.5 Hz), 1.70 (2H, m), 2.73 (2H, t,J=7.5 Hz), 3.40 (3H, s), 5.42 (2H, s), 6.23 (1H, d, J=7.5 Hz), 6.91 (1H,d, J=7.5 Hz), 6.98 (1H, m), 7.15-7.25 (3H, m), 7.36 (1H, t, J=7.5 Hz),7.46-7.57 (3H, m), 8.23 (1H, m).

mp: 143-146° C.

EXAMPLE 17-111-(2-Chlorobenzyl)-6-(homopiperidinocarbonyl)-2-n-propylbenzimidazole(78)

Properties of Compound (78):

¹ H-NMR (CDCl₃, δ): 1.03 (3H, t, J=7.5 Hz), 1.46-1.94 (10H, m), 2.80(2H, t, J=7.5 Hz), 3.32 (2H, brs), 3.64 (2H, t, J=7.5 Hz), 5.41 (2H, s),6.42 (1H, d, J=7.5 Hz), 7.07 (1H, t, J=7.5 Hz), 7.19-7.29 (3H, m), 7.45(1H, d, J=7.5 Hz), 7.76 (1H, d, J=7.5 Hz).

mp: 136-137° C.

EXAMPLE 17-121-(3-Methylbenzyl)-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(79)

Properties of Compound (79):

¹ H-NMR (CDCl₃, δ): 1.02 (3H, t, J=7.5 Hz), 1.88 (2H, m), 2.26 (3H, s),2.81 (2H, t, J=7.5 Hz), 4.76 (2H, d, J=5 Hz), 5.36 (2H, s), 6.78-6.84(2H, m), 7.07 (1H, d, J=7.5 Hz), 7.13-7.22 (2H, m), 7.33 (1H, d, J=7.5Hz), 7.57-7.72 (2H, m), 7.78 (1H, d, J=7.5 Hz), 7.94 (1H, s), 8.55 (1H,d, J=5 Hz).

mp: 129-131° C.

EXAMPLE 17-132-n-Butyl-1-(2-fluorobenzyl)-6-[N-methyl-N-(2-pyridylmethyl)carbamoyl]benzimidazole(80)

Properties of Compound (80):

¹ H-NMR (CDCl₃, δ): 0.92 (3H, t, J=7.5 Hz), 1.45 (2H, m), 1.83 (2H, m),2.86 (2H, t, J=7.5 Hz), 3.06 (3H, brs), 4.61 (1H, brs), 4.86 (1H, brs),5.37 (2H, brd), 6.62 (1H, brd), 6.97 (1H, brs), 7.07-7.85 (8H, m), 8.57(1H, d, J=5 Hz).

mp: 97-100° C.

EXAMPLE 17-141-(2-Chlorobenzyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(81)

Properties of Compound (81):

¹ H-NMR (CDCl₃, δ): 1.43 (3H, t, J=7.5 Hz), 2.84 (2H, q, J=7.5 Hz), 4.76(2H, d, J=5 Hz), 5.45 (2H, s), 6.37 (1H, d, J=7.5 Hz), 7.07 (1H, t,J=7.5 Hz), 7.19-7.28 (2H, m), 7.33 (1H, d, J=7.5 Hz), 7.45 (1H, dd,J=7.5 and 2 Hz), 7.62-7.75 (3H, m), 7.82 (1H, d, J=7.5 Hz), 7.89 (1H, d,J=2 Hz), 8.55 (1H, d, J=5 Hz).

mp: 167-168° C.

EXAMPLE 17-152-n-Butyl-1-(2-chlorobenzyl)-7-[(2-pyridylmethyl)carbamoyl]benzimidazole(82)

Properties of Compound (82):

¹ H-NMR (CDCl₃, δ): 0.93 (3H, t, J=7.5 Hz), 1.42 (2H, m), 1.83 (2H, m),2.81 (2H, t, J=7.5 Hz), 4.44 (2H, d, J=5 Hz), 5.70 (2H, s), 6.13 (1H,dd, J=7.5 and 2 Hz), 6.85-6.97 (3H, m), 7.12-7.28 (4H, m), 7.34 (1H, d,J=7.5 Hz), 7.62 (1H, dt, J=7.5 and 2 Hz), 7.88 (1H, d, J=7.5 Hz), 8.40(1H, d, J=5 Hz).

mp: 112-114° C.

EXAMPLE 17-162-Cyclopropyl-1-(2-fluorobenzyl)-6-(piperonylcarbamoyl)benzimidazole(83)

Properties of Compound (83):

¹ H-NMR (DMSO-d6, δ): 1.05 (4H, m), 2.27 (1H, m), 4.38 (2H, d, J=5 Hz),5.71 (2H, s), 5.98 (2H, s), 6.73-6.91 (4H, m), 7.14 (1H, t, J=7.5 Hz),7.27 (1H, t, J=7.5 Hz), 7.36 (1H, m), 7.55 (1H, d, J=7.5 Hz), 7.73 (1H,dd, J=7.5 and 2 Hz), 8.04 (1H, s), 8.87 (1H, t, J=5 Hz).

mp: 170-173° C.

EXAMPLE 17-172-[[1-(2-chlorobenzyl)-2-ethylbenzimidazol-6-yl]carbonylaminomethyl]-pyridine-1-oxide(84)

Properties of Compound (84):

¹ H-NMR (CDCl₃, δ): 1.42 (3H, t, J=7.5 Hz), 2.82 (2H, q, J=7.5 Hz), 4.81(2H, d, J=7.5 Hz), 5.43 (2H, s), 6.31 (1H, d, J=7.5 Hz), 7.06 (1H, t,J=7.5 Hz), 7.20-7.31 (3H, m), 7.44 (1H, d, J=7.5 Hz), 7.52 (1H, dd,J=7.5 and 2 Hz), 7.65 (1H, dd, J=7.5 and 2 Hz), 7.77-7.83 (2H, m), 7.96(1H, t, J=7.5 Hz), 8.23 (1H, dd, J=7.5 and 2 Hz).

mp: 204-207° C.

EXAMPLE 17-182-n-Butyl-1-(2-fluorobenzyl)-6-(2-pyridylmethylcarbamoyl)benzimidazole(85)

Properties of Compound (85):

¹ H-NMR (CDCl₃, δ): 0.92 (3H, t, J=7.5 Hz), 1.38-1.49 (2H, m), 1.77-1.88(2H, m), 2.86 (2H, t, J=7.5 Hz), 4.78 (2H, d, J=5 Hz), 5.46 (2H, s),6.67 (1H, t, J=9 Hz), 7.00 (1H, t, J=9 Hz), 7.13 (1H, t, J=9 Hz),7.19-7.31 (2H, m), 7.33 (1H, d, J=9 Hz), 7.60 (1H, br peak), 7.65-7.74(2H, m), 7.79 (1H, d, J=9 Hz), 7.97 (1H, d, J=2 Hz), 8.58 (1H, d, J=5Hz).

mp: 154-155° C.

EXAMPLE 18 Synthesis of6-tert-buthoxycabonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole(86)

Two-hundred milligrams of6-carboxy-1-(2-chlorobenzyl)-2-n-propylbenzimidazole were suspended in 5ml of tert-butyl alcohol, and 0.19 ml of diphenylphosphorylazide and0.21 ml of diisopropylethylamine were added thereto at room temperature.The reaction mixture was refluxed for 4 hours, and was then separatedwith ethyl acetate and with water. The organic layer was washed withwater, dried, and then concentrated under reduced pressure. The residuewas developed and purified through column chromatography using a mixtureof ethyl acetate and hexane (at a ratio of from 1:10 to 1:3), and wasfurther recrystallized from a mixture of ethyl acetate and hexane togive 165 mg of6-tert-buthoxycabonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole(86).

Properties of Compound (86):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 0.98 (3H, t, J=8 Hz), 1.50 (9H, s), 1.86 (2H,sextet, J=8 Hz), 2.72 (2H, t, J=8 Hz), 5.38 (2H, s), 6.40 (1H, dd, J=1,8 Hz), 6.95 (1H, dd, J=1, 10 Hz), 7.08 (1H, dt, J=1, 8 Hz), 7.24 (1H,dt, J=1, 8 Hz), 7.28 (1H, d, J=1 Hz), 7.45 (1H, dd, J=1, 8 Hz), 7.66(1H, d, J=10 Hz).

mp: 166-168° C.

EXAMPLE 19 Synthesis of1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole (87)

A solution of 1 mol of titanium tetrachloride in 0.14 ml ofdichloromethane and 0.36 ml of triethylamine were added to a solution of200 mg of 6-carbamoyl-1-(2-chlorobenzyl)-2-n-propylbenzimidazole in 4 mlof tetrahydrofuran at ⁰° C., and the mixture was stirred at 20° C. for 2hours. The reaction mixture was separated with ethyl acetate and withwater. The organic layer was washed with water, dried, and thenconcentrated under reduced pressure. The residue was developed andpurified through column chromatography using a mixture of ethyl acetateand hexane (at a ratio of from 1:10 to 1:3), and was furtherrecrystallized from a mixture of ethyl acetate and hexane to give 140 mgof 1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole (87).

Properties of Compound (87):

colorless crystal.

¹ H-NMR (CDCl₃, δ): 1.05 (3H, t, J=8 Hz), 1.90 (2H, sextet, J=8 Hz),2.85 (2H, t, J=8 Hz), 5.45 (2H, s), 6.42 (1H, dd, J=1, 8 Hz), 7.15 (1H,dt, J=1, 8 Hz), 7.28 (1H, dt, J=1, 8 Hz), 7.48 (1H, s), 7.50 (1H, d,J=10 Hz), 7.54 (1H, dd, J=1, 8 Hz), 7.85 (1H, d, J=10 Hz).

mp: 124-126° C.

EXAMPLE 20 Synthesis of1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole (88)

1-(2-Chlorobenzyl)-2-n-propylbenzimidazole (150 mg) and 61 mg oftriethylamine were dissolved in 3 ml of methylene chloride, and 70 mg ofmethanesulfonyl chloride were added thereto at room temperature. Themixture was stirred for 1 hour, then washed with dilute hydrochloricacid, washed with water, and dried. The solvent was distilled off underreduced pressure. The residual solid was collected with ether throughfiltration to give 124 mg of1-(2-chlorobenzyl)-6-mesylamino-2-n-propylbenzimidazole (88).

Properties of Compound (88):

¹ H-NMR (CDCl₃ --CD3OD, δ): 0.94 (3H, t, J=7.5 Hz), 1.76 (2H, m), 2.71(2H, t, J=7.5 Hz), 2.81 (3H, s), 5.36 (2H, s), 6.40 (1H, d, J=7.5 Hz),6.98-7.22 (4H, m), 7.40 (1H, d, J=7.5 Hz), 7.59 (1H, d, J=7.5 Hz).

mp: 191-193° C.

EXAMPLE 21 Synthesis of6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (89)

Acetic anhydride (62 mg) was added to a solution of 150 mg of6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole and 61 mg oftriethylamine in 3 ml of methylene chloride at room temperature, and themixture was stirred for 1 hour. The reaction mixture was washed withwater, and was then dried. The solvent was distilled off under reducedpressure. The residue was crystallized with ether to give 143 mg of6-acetylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (89).

Properties of Compound (89):

¹ H-NMR (CDCl₃, δ): 1.00 (3H, t, J=7.5 Hz), 1.86 (2H, m), 2.17 (3H, s),2.73 (2H, t, J=7.5 Hz), 5.39 (2H, s), 6.43 (1H, d, J=7.5 Hz), 6.98-7.11(2H, m), 7.22 (1H, t, J=7.5 Hz), 7.45 (1H, d, J=7.5 Hz), 7.59 (1H, brs),7.68 (1H, d, J=7.5 Hz), 7.84 (1H, d, J=1.5 Hz).

mp: 180-182° C.

EXAMPLE 22 Synthesis of6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (90)

Seven-hundred milligrams of6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-n-propylbenzimidazolewere dissolved in a mixed solvent of 10 ml of methylene chloride and 1ml of trifluoroacetic acid, and the mixture was stirred at roomtemperature for 5 hours. A small amount of methylene chloride was addedto the reaction solution. The mixture was washed with a sodium carbonateaqueous solution, and was dried. The solvent was then distilled off. Theresidue was crystallized from a mixed solvent of n-hexane and ether togive 455 mg of 6-amino-1-(2-chlorobenzyl)-2-n-propylbenzimidazole (90).

Properties of Compound (90):

¹ H-NMR (CDCl₃, δ): 1.01 (3H, t, J=7.5 Hz), 1.86 (2H, m), 2.73 (2H, t,J=7.5 Hz), 5.30 (2H, s), 6.41 (1H, d, J=1.5 Hz), 6.48 (1H, d, J=7.5 Hz),6.66 (1H, dd, J=7.5 and 1.5 Hz), 7.10 (1H, t, J=7.5 Hz), 7.25 (1H, t,J=7.5 Hz), 7.46 (1H, d, J=7.5 Hz), 7.57 (1H, d, J=7.5 Hz).

mp: 121-122° C.

EXAMPLE 23 Synthesis of1-(2-chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole (91)

1-(2-Chlorobenzyl)-2-n-propyl-6-ureidobenzimidazole (91) was formed inthe same manner as in Example 21.

Properties of Compound (91):

¹ H-NMR (DMSO-d6, δ): 0.93 (3H, t, J=7.5 Hz), 1.72 (2H, m), 2.73 (2H, t,J=7.5 Hz), 5.43 (2H, s), 5.73 (2H, s), 6.42 (1H, dd, J=7.5 and 1.5 Hz),7.05 (1H, dd, J=7.5 and 1.5 Hz), 7.22 (1H, dt, J=7.5 and 1.5 Hz), 7.33(1H, dt, J=7.5 and 1.5 Hz), 7.45 (1H, d, J=7.5 Hz), 7.50 (1H, s), 7.57(1H, dd, J=7.5 and 1.5 Hz), 8.50 (1H, s).

mp: 198° C.

PRODUCTION EXAMPLE 12 Production of ethyl 3-acetylamino-4-nitrobenzoate

Nine milliliters of acetyl chloride were added to a mixture of 18.4 g ofethyl 3-amino-4-nitrobenzoate and 200 ml of N,N-dimethylaniline whilebeing cooled with ice. The mixture was stirred at room temperature for 2hours and then at 50° C. for 2 hours. The reaction solution was pouredinto cold 1-N hydrochloric acid, and the mixture was extracted twicewith ethyl acetate. The organic layer was washed with 1-N hydrochloricacid and then with water, and was dried. The solvent was then distilledoff under reduced pressure. The residue was purified through silica-gelcolumn chromatography (eluent: a mixture of ethyl acetate and hexane ata ratio of from 1:10 to 1:4) to give 19.6 g of ethyl3-acetylamino-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.42(3H, t, J=7.1 Hz), 2.32(3H, s), 4.43(2H, q, J=7.1Hz), 7.82(1H, dd, J=1.8 and 8.7 Hz), 8.25(1H, d, J=8.7 Hz), 9.35(1H, d,J=1.8 Hz), 10.19(1H, s).

PRODUCTION EXAMPLE 13 Production of ethyl4-nitro-3-phenylacetylaminobenzoate

In the same manner as in Production Example 12, 3.30 g of ethyl4-nitro-3-phenylacetylaminobenzoate were formed from 2.02 g of ethyl3-amino-4-nitrobenzoate and 1.87 g of phenylacetyl chloride.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=7.2 Hz), 3.85(2H, s), 4.42(2H, q, J=7.2Hz), 7.34-7.49(5H, m), 7.79(1H, m), 8.19(1H, d, J=8.7 Hz), 9.39(1H, d,J=1.6 Hz), 10.15(1H, s).

PRODUCTION EXAMPLE 14 Production of ethyl3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzoate

A solution of 1.706 g of ethyl 3-acetylamino-4-nitrobenzoate in 12 ml ofN,N-dimethylformamide were added 0.406 g of 60% sodium hydride whilebeing cooled with ice, and the mixture was stirred at room temperaturefor 40 minutes. A solution of 1.806 g of 2-chlorobenzyl bromide in 10 mlof N,N-dimethylformamide was added thereto, and the mixture was stirredat room temperature for 3 hours. The reaction mixture was poured intocold 1-N hydrochloric acid, and the mixed solution was extracted twicewith ethyl acetate. The organic layer was washed with 1-N hydrochloricacid and then with water, and was dried. The solvent was distilled offunder reduced pressure. The residue was purified through silica-gelcolumn chromatography (eluent: a mixture of ethyl acetate and hexane ata ratio of from 1:10 to 1:4) to give 2.08 g of oily ethyl3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.1 Hz), 1.92(3H, s), 4.28-4.45(2H, m),4.72(1H, d, J=14.5 Hz), 5.34(1H, d, J=14.5 Hz), 7.16-7.44(4H, m),7.69(1H, d, J=1.7 Hz), 7.94(1H, d, J=8.4 Hz), 8.13(1H, dd, J=1.7 and 8.4Hz).

PRODUCTION EXAMPLE 15 Production of ethyl4-nitro-3-[N-[2-(trifluoromethyl)benzyl]acetylamino]benzoate

In the same manner as in Production Example 14, 1.82 g of ethyl4-nitro-3-[N-[2-(trifluoromethyl)-benzyl]acetylamino]benzoate wereformed from 1.49 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.69 g of2-(trifluoromethyl)benzyl bromide.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.37(3H, t, J=7.1 Hz), 1.96(3H, s), 4.29-4.42(2H, m),4.78(1H, d, J=15.4 Hz), 5.40(1H, d, J=15.4 Hz), 7.38(1H, t, J=7.6 Hz),7.51-7.58(2H, m), 7.61(1H, d, J=1.7 Hz), 7.67(1H, d, J=7.8 Hz), 7.92(1H,d, J=8.4 Hz), 8.13(1H, dd, J=1.7 and 8.4 Hz).

mp: 153.5-158.0° C.

PRODUCTION EXAMPLE 16 Production of ethyl4-nitro-3-[N-[4-(trifluoromethyl)benzyl]acetylaminobenzoate

In the same manner as in Production Example 14, 1.52 g of ethyl4-nitro-3-[N-[4-(trifluoromethyl)-benzyl]acetylaminobenzoate were formedfrom 1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.71 g of4-(trifluoromethyl)benzyl bromide.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.36(3H, t, J=7.1 Hz), 1.91(3H, s), 4.32-4.43(2H, m),4.42(1H, d, J=14.6 Hz), 5.33(1H, d, J=14.6 Hz), 7.30(2H, d, J=8.1 Hz),7.54(2H, d, J=8.1 Hz), 7.61(1H, d, J=1.8 Hz), 7.96(1H, d, J=8.4 Hz),8.12(1H, dd, J=1.8 and 8.4 Hz).

PRODUCTION EXAMPLE 17 Production of 2-cyanobenzyl3-[N-(2-cyanobenzyl)acetylamino]-4-nitrobenzoate

A solution of 1.50 g of 3-acetylamino-4-nitrobenzoic acid in 10 ml ofN,N-dimethylformamide was added dropwise to a slurry of 0.802 g of 60%sodium hydride and 10 ml of N,N-dimethylformamide at room temperature,and the mixture was stirred for 30 minutes. Subsequently, a solution of3.93 g of 2-cyanobenzyl bromide in 10 ml of N,N-dimethylformamide wasadded dropwise thereto, and the mixture was stirred for 30 minutes.Ethyl acetate was poured into the reaction solution, and the crystalsprecipitated were separated through filtration. The crystals obtainedwere washed with ethyl acetate, and were further dissolved inchloroform. The filtrate from which the solid component was removed wasconcentrated to give 1.96 g of yellow crystals of 2-cyanobenzyl3-[N-(2-cyanobenzyl)acetylamino]-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.92(3H, s), 4.92(1H, d, J=4.8 Hz), 5.24(2H, d, J=4.9Hz), 5.44(2H, dd, J=7.9 and 2.9 Hz), 7.36(1H, t, J=7.5 Hz), 7.47(1H, d,J=7.7 Hz), 7.52(1H, t, J=7.7 Hz), 7.56-7.62(2H, m), 7.63-7.71(2H, m),7.76(1H, d, J=7.8 Hz), 7.80(1H, d, J=1.7 Hz), 7.99(1H, d, J=8.4 Hz),8.25(1H, dd, J=8.4 and 1.8 Hz).

PRODUCTION EXAMPLE 18 Production of ethyl4-amino-3-(N-i-propylbutyrylamino)benzoate

A solution of 2.00 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml ofN,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60%sodium hydride and 10 ml of N,N-dimethylformamide at room temperature,and the mixture was stirred for 30 minutes. A solution of 1.46 g ofisopropyl iodide in 10 ml of N,N-dimethylformamide was then addeddropwise thereto, and the mixture was stirred at 100° C. for 5 days. Thereaction solution was poured into a mixed solution of 80 g of dilutehydrochloric acid and 80 g of ethyl acetate for separation. Theresulting organic layer was washed with 50 g of water, and was thenconcentrated under reduced pressure. The residue was purified throughsilica-gel column chromatography (eluent: a mixture of hexane and ethylacetate at a ratio of 4:1) to obtain 0.260 g of crude ethyl4-nitro-3-(N-i-propylbutyrylamino)benzoate. Subsequently, 3 ml ofethanol and 2 ml of acetic acid were added to 0.260 g of ethyl4-nitro-3-(N-i-propylbutyrylamino)benzoate at room temperature, and0.519 g of reduced iron were further added thereto. The mixture washeat-refluxed for 4 hours. The solid material was removed using afiltration aid, and the filtrate was concentrated. The residue wereadded 30 ml of ethyl acetate and 30 ml of dilute hydrochloric acid forseparation. The organic layer was washed with 30 ml of water, and wasthen concentrated under reduced pressure. The residue was purifiedthrough preparative thin-layer silica-gel chromatography (developingeluent: a mixture of hexane and ethyl acetate at a ratio of 1:1) to give0.06 g of ethyl 4-amino-3-(N-i-propylbutyrylamino)benzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 0.82(3H, t, J=7.4 Hz), 1.01(3H, d, J=6.9 Hz),1.24(3H, d, J=6.6 Hz), 1.38(3H, t, J=7.0 Hz), 1.54-1.62(2H, m),1.87-2.04(2H, m), 4.34(2H, q, J=7.0 Hz), 4.45(2H, s), 4.88-4.96(1H, m),6.78(1H, d, J=8.4 Hz), 7.64(1H, d, J=1.9 Hz), 7.87(1H, dd, J=8.4 and 1.9Hz).

PRODUCTION EXAMPLE 19 Production of ethyl3-nitro-4-phenylacetylaminobenzoate

In the same manner as in Production example 12, 6.00 g of ethyl3-nitro-4-phenylacetylaminobenzoate were formed from 4.04 g of ethyl4-amino-3-nitrobenzoate and 3.74 g of phenylacetyl chloride.

PRODUCTION EXAMPLE 20 Production ofN-benzenesulfonyl-3-amino-4-nitrobenzamide

N,N'-carbonyldiimidazole (28.9 g) was added to a solution of 20.0 g of3-acetylamino-4-nitrobenzoic acid in 300 ml of N,N-dimethylformamide,and the mixture was stirred at room temperature for 1 hour. Further,28.00 g of benzenesulfonamide and 27.16 g of diazabicycloundecene wereadded thereto, and the mixture was stirred at 100° C. for 4 days. Thesolvent was distilled off under reduced pressure. Chloroform and a 10%sodium hydroxide aqueous solution were added to the residue, and themixture was vigorously stirred. The aqueous layer was neutralized with10% hydrochloric acid, and the mixture was vigorously stirred with theaddition of chloroform. The crystals precipitated were separated throughfiltration, and were dried to 14.4 g ofN-benzenesulfonyl-3-amino-4-nitrobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 6.93(1H, dd, J=1.8 and 9.0 Hz), 7.43(1H, d, J=1.8Hz), 7.52(2H, br s), 7.65(2H, t, J=7.5 Hz), 7.74(1H, t, J=7.5 Hz),7.98-7.82(3H, m), 12.74(1H, s).

PRODUCTION EXAMPLE 21 Production ofN-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamidepotassium salt

A solution of 10.0 g of N-benzenesulfonyl-3-amino-4-nitrobenzamide in150 ml of methanol were added 56.5 g of a 20% potassiumhydrogencarbonate aqueous solution and 11.5 g of 4-bromomethylbiphenyl,and the mixture was stirred at 70° C. for 3 hours. The mixture wascooled, and the crystals precipitated were collected through filtration,and were dried to give 4.27 g ofN-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamidepotassium salt.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 4.65(2H, d, J=5.8 Hz), 7.19(1H, d, J=8.9 Hz),7.33-7.42(4H, m), 7.57-7.71(4H, m), 7.75-7.81(2H, m), 8.02(1H, d, J=8.9Hz), 8.61(1H, br t).

IR(Nujol): 1598 cm⁻¹.

PRODUCTION EXAMPLE 22 Production ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamidepotassium salt

Five-percent palladium on carbon (0.64 g) was added to a mixturecontaining 4.27 g ofN-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-nitrobenzamidepotassium salt, 10.7 g of a 20% potassium hydrogencarbonate aqueoussolution and 200 ml of methanol, and the mixture was stirred in ahydrogen atmosphere at 35° C. for 14 hours. The crystals precipitatedwere dissolved in 400 ml of a mixed solution of acetone and water (at aratio of 5:2). The solid material was separated through filtration. Thefiltrate was concentrated, and the crystals precipitated were separatedthrough filtration, and were dried to give 3.15 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamidepotassium salt.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 4.31(2H, d, J=5.7 Hz), 4.85(2H, s), 4.91(1H, br t,J=5.7 Hz), 6.45(1H, d, J=7.9 Hz), 7.07(1H, s), 7.13(1H, d, J=7.9 Hz),7.29-7.36(4H, m), 7.43-7.47(4H, m), .7.60(2H, d, J=8.1 Hz), 7.65(2H, d,J=7.6 Hz), 7.73-7.76(2H, m).

IR(Nujol): 1574 cm⁻¹.

PRODUCTION EXAMPLE 23 Production ofN-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide

Oxalyl chloride (1.25 g) was added dropwise to a solution of 1.00 g of4-acetylamino-3-nitrobenzoic acid and 0.20 g of N,N-dimethylformamide in15 ml of methylene chloride while being cooled with ice. The mixture wasfurther stirred at room temperature for 1 hour. The reaction solutionwas concentrated, and diisopropyl ether was added thereto forcrystallization. The crystals were added to a solution of 0.483 g of2-aminomethylpyridine and 0.35 g of triethylamine in 15 ml of methylenechloride. After the mixture was stirred at room temperature for 1 hour,the organic layer was washed twice with water (100 ml×2) and then with100 ml of a sodium hydrogencarbonate aqueous solution. The organic layerwas concentrated to give 0.99 g ofN-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.33(3H, s), 4.76(2H, d, J=4.8 Hz), 7.25(1H, dd,J=5.0 and 7.2 Hz), 7.34(1H, d, J=7.9 Hz), 7.71(1H, dt, J=1.8 and 7.8Hz), 7.84(1H, s), 8.14(1H, dd, J=2.1 and 8.8 Hz), 8.58(1H, d, J=4.9 Hz),8.77(1H, d, J=2.1 Hz), 8.90(1H, d, J=8.0 Hz), 10.47(1H, s).

PRODUCTION EXAMPLE 24 Production ofN-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide

Five-percent palladium on carbon (2.53 g) was added to a solution of10.0 g of N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide in 150 mlof methanol, and the mixture was stirred in a hydrogen atmosphere at 60°C. for 15 hours. The solid material was separated through filtration,and the filtrate was concentrated. The resulting residue was purifiedthrough silica-gel column chromatography (eluent: a mixture of ethylacetate and methanol at a ratio of 7:3) to give 8.02 g ofN-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.06(3H, s), 4.52(2H, d, J=5.9 Hz), 5.09(2H, s),7.10(1H, dd, J=1.9 and 8.2 Hz), 7.22-7.30(3H, m), 7.38(1H, d, J=8.2 Hz),7.75(1H, dt, J=1.7 and 7.6 Hz), 8.50(1H, d, J=4.6 Hz), 8.84(1H, t, J=5.8Hz), 9.19(1H, s).

PRODUCTION EXAMPLE 25 Production ofN-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide

A solution of 0.80 g ofN-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml ofN,N-dimethylformamide were added 1.31 g of 4-benzyloxybenzyl chlorideand 1.18 g of sodium hydrogencarbonate, and the mixture was stirred at90° C. for 2 hours. Chloroform and water were added to the reactionsolution, and the chloroform extraction was conducted. The organic layerwas washed with water, concentrated, and purified through silica-gelcolumn chromatography to give 0.434 g ofN-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.07(3H, s), 4.30(2H, d, J=5.6 Hz), 4.51(2H, d,J=5.9 Hz), 5.07(2H, s), 5.68(1H, t, J=5.6 Hz), 6.97(2H, d, J=8.6 Hz),7.14(2H, m), 7.25(2H, dd, J=3.4 and 7.4 Hz), 7.32(4H, t, 7.5 Hz),7.38(2H, t, J=7.1 Hz), 7.44(2H, d, J=7.2 Hz), 7.72(1H, dt, J=1.8 and 7.7Hz), 8.49(1H, dd, J=1.9 and 5.3 Hz), 8.89(1H, t, J=5.9 Hz), 9.28(1H, s).

PRODUCTION EXAMPLE 26 Production ofN-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide

A solution of 0.80 g ofN-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml ofN,N-dimethylformamide were added 0.962 g of 3,4-methylenedioxybenzylchloride and 0.710 g of sodium hydrogencarbonate, and the mixture wasstirred at 80° C. for 4 hours. Chloroform and water were added to thereaction solution, and the chloroform extraction was conducted. Theorganic layer was washed with water, concentrated, and purified throughsilica-gel column chromatography (eluent: a mixture of ethyl acetate andmethanol at a ratio of 9:1) to give 0.49 g ofN-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.08(3H, s), 4.29(2H, s), 4.52(2H, d, J=5.9 Hz),5.27(1H, s), 5.97(2H, s), 6.84-6.88(2H, m), 6.96(1H, s), 7.10(1H, d,J=1.3 Hz), 7.13(1H, dd, J=1.6 and 8.2 Hz), 7.25-7.32(3H, m), 7.76(1H,dt, J=1.2 and 7.6 Hz), 8.51(1H, d, J=4.8 Hz), 8.90(1H, t, J=5.8 Hz),9.28(1H, s).

PRODUCTION EXAMPLE 27 Production ofN-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide

A solution of 0.800 g ofN-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of methanolwere added 1.08 g of 4-(4-bromomethylphenyl)-1,2,3-thiadiazole and 0.710g of sodium hydrogencarbonate, and the mixture was stirred at 70° C. for1 hour. The reaction solution was concentrated, and was purified throughsilica-gel column chromatography (eluent: a mixture of ethyl acetate andmethanol at a ratio of 9:1) to give 0.830 g ofN-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.11(3H, s), 4.43-5.56(2H, m), 5.92(1H, t, J=5.9 Hz),7.51(1H, d, J=1.4 Hz), 7.15(1H, dd, J=1.6 and 8.1 Hz), 7.22(2H, dd,J=1.9 and 8.1 Hz), 7.33(1H, d, J=8.1 Hz), 7.57(2H, d, J=8.1 Hz),7.69(1H, dt, J=1.8 and 7.7 Hz), 8.09(2H, d, J=8.2 Hz), 8.47(1H, dd,J=1.9 and 5.2 Hz), 8.89(1H, t, J=5.9 Hz), 9.34(1H, s), 9.58(1H, s).

PRODUCTION EXAMPLE 28 Production ofN-benzenesulfonyl-4-acetylamino-3-nitrobenzamide

N,N'-carbonyldiimidazole (14.45 g) was added to a solution of 10.00 g of4-acetylamino-3-nitrobenzoic acid in 300 ml of N,N-dimethylformamide,and the mixture was stirred at room temperature for 1 hour.Subsequently, 14.03 g of benzenesulfonamide and 13.58 g ofdiazabicycloundecene were added thereto, and the mixture was stirred at100° C. for 72 hours. The reaction mixture was separated with theaddition of chloroform and water. The organic layer was thenconcentrated, and the resulting residue was purified through silica-gelcolumn chromatography (eluent: a mixture of ethyl acetate and methanolat a ratio of 4:1) to give 12.67 g ofN-benzenesulfonyl-4-acetylamino-3-nitrobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.08(3H, s), 7.39-7.47(3H, m), 7.65(1H, d, J=8.5Hz), 7.84(2H, dd, J=1.4 and 7.7 Hz), 8.11(1H, dd, J=1.9 and 8.4 Hz),8.38(1H, d, J=1.9 Hz), 10.34(1H, s).

PRODUCTION EXAMPLE 29 Production ofN-benzenesulfonyl-4-acetylamino-3-aminobenzamide

N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide (12.67 g) was dissolvedin 200 ml of methanol and 30 ml of water, and 7.59 g of potassiumhydrogencarbonate were further added thereto. The mixture washydrogenated in a hydrogen atmosphere using 2.53 g of 5% palladium oncarbon as catalyst at 40° C. for 24 hours. The solid material wasseparated through filtration, and the filtrate was concentrated. Theresulting residue was purified through silica-gel column chromatography(eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) togive 6.72 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.06(3H, s), 7.07(1H, dd, J=1.8 and 8.3 Hz),7.17(1H, d, J=1.8 Hz), 7.44(1H, d, J=8.3 Hz), 7.61(2H, t), 7.68(1H, t),7.96(2H, d, J=7.5 Hz), 9.19(1H, s).

IR(Nujol): 1682 cm⁻¹.

PRODUCTION EXAMPLE 30 Production ofN-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzylamino)benzamide

In the same manner as in Production Example 32, 0.79 g ofN-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzylamino)benzamide wereformed from 0.60 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamideand 0.52 g of 2-nitrobenzyl bromide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.08(3H, s), 4.72(2H, d, J=5.0 Hz), 5.92(1H, s),6.86(1H, s), 7.13(1H, d, J=8.1 Hz), 7.31(1H, d, J=8.0 Hz), 7.49-7.58(3H,m), 7.60(2H, d, J=7.6 Hz), 7.66(1H, t, J=7.4 Hz), 7.86(2H, d, J=7.7 Hz),8.11(1H, d, J=8.3 Hz), 9.37(1H, s).

PRODUCTION EXAMPLE 31 Production ofN-benzenesulfonyl-4-acetylamino-3-benzylaminobenzamide

In the same manner as in Production Example 32, 0.38 g ofN-benzenesulfonyl-4-acetylamino-3-benzylaminobenzamide were formed from0.60 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide and 0.47 g ofbenzyl bromide.

Properties of the compound:

¹ H-NMR (DMSO-d6, δ): 2.07 (3H, s), 4.35(2H, d, J=5.5 Hz), 5.73(1H, s),7.06(1H, s), 7.14(1H, d, J=8.3 Hz), 7.21-7.28(2H, m), 7.32(2H, t, J=7.3Hz), 7.37(2H, d, J=7.6 Hz), 7.53(2H, t, J=7.4 Hz), 7.59(1H, t, J=7.0Hz), 7.88(2H, d, J=7.7 Hz), 9.29(1H, s), 12.34(1H, s).

PRODUCTION EXAMPLE 32 Production ofN-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide

A solution of 7 ml of methanol containing 0.60 g ofN-benzenesulfonyl-4-acetylamino-3-aminobenzamide, 0.656 g of2,4-difluorobenzyl bromide and 0.423 g of potassium hydrogencarbonatewas stirred at 60° C. for 1 hour. The reaction solution wasconcentrated, and the residue was purified through silica-gel columnchromatography (eluent: a mixture of ethyl acetate and methanol at aratio of 9:1) to give 0.370 g ofN-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.05(3H, s), 4.34(2H, d, J=5.5 Hz), 5.60(1H, s),7.02(1H, t, J=8.0 Hz), 7.06(1H, s), 7.16-7.27(3H, m), 7.38-7.51(4H, m),7.82(2H, d, J=7.2 Hz), 9.27(1H, s), 12.35(1H, s).

PRODUCTION EXAMPLE 33 Production ofN-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide

In the same manner as in Production Example 32, 0.52 g ofN-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide wereformed from 0.50 g of N-benzenesulfonyl-4-acetylamino-3-aminobenzamideand 0.436 g of 4-nitrobenzyl bromide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.09(3H, s), 4.54(2H, d, J=5.0 Hz), 6.10(1H, s),6.89(1H, d, J=1.8 Hz), 7.14(1H, dd, J=1.8 and 8.2 Hz), 7.39(1H, d, J=8.2Hz), 7.58-7.65(4H, m), 7.68(1H, t, J=7.6 Hz), 7.92(2H, dd, J=1.4 and 7.4Hz), 8.20(2H, d, J=8.7 Hz), 9.36(1H, s), 12.28(1H, s).

PRODUCTION EXAMPLE 34 Production ofN-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide

In the same manner as in Production Example 32, 0.38 g ofN-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamidewere formed from 0.50 g ofN-benzenesulfonyl-4-acetylamino-3-aminobenzamide and 0.45 g of4-(4-bromomethylphenyl)-1,2,3-thiadiazole.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 2.10(3H, s), 4.46(2H, d, J=5.3 Hz). 5.96(1H, s),7.03(1H, s), 7.14(1H, dd, J=1.7 and 8.2 Hz), 7.40(1H, d, J=8.0 Hz),7.52-7.61(4H, m), 7.65(1H, t, J=7.1 Hz), 7.93(2H, d, J=7.6 Hz), 8.10(2H,d, J=8.2 Hz), 9.35(1H, s), 9.58(1H, s), 12.31(1H, s).

PRODUCTION EXAMPLE 35 Production of ethyl 3-amino-2-nitrobenzoate

A mixture of 20.2 g of 3-acetylamino-2-nitrobenzoic acid, 11.4 g of 97%sulfuric acid and 300 ml of ethanol was stirred for 23 hours while beingheat-refluxed. One-hundred milliliters of ethanol were distilled offunder reduced pressure, and the residue was cooled to room temperature.Subsequently, the reaction solution was poured into 200 ml of ice watercontaining 19.5 g of sodium hydrogencarbonate. The crystals precipitatedwere separated through filtration, and were washed with water. Further,these crystals were dispersed in 30 ml of a mixed solution of ethylacetate and hexane at a ratio of 1:2. The crystals were separatedthrough filtration, washed with hexane, and then dried to give 18.0 g ofethyl 3-amino-2-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 4.37(2H, q, J=7.1 Hz),6.41(2H, br s), 6.83(1H, d, J=8.7 Hz), 8.00(1H, dd, J=1.8 and 8.7 Hz),8.85(1H, d, J=1.8 Hz).

PRODUCTION EXAMPLE 36 Production of ethyl 3-acetylamino-2-nitrobenzoate

Acetyl chloride (13 ml) was added dropwise to a solution of 2.98 g ofethyl 3-amino-2-nitrobenzoate and 20 ml of N,N-dimethylaniline in an icebath. The mixture was stirred at room temperature for 48 hours. Thereaction solution was acidified with 10% hydrochloric acid, and wasextracted twice with ethyl acetate. The organic layer was washed threetimes with water. The solvent was distilled off under reduced pressure,and the resulting residue was crystallized with hexane. The crystalswere separated through filtration, washed with hexane, and dried to give3.30 g of ethyl 3-acetylamino-2-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.42(3H, t), 2.33(3H, s), 4.42(2H, q), 8.27(1H, dd,J=1.9 and 8.9 Hz), 8.89(1H, d, J=1.9 Hz), 8.91(1H, d, J=8.9 Hz),10.54(1H, br s).

PRODUCTION EXAMPLE 37 Production of ethyl 4-acetylamino-3-aminobenzoate

A mixture of 149.4 g of ethyl 3-acetylamino-2-nitrobenzoate, 14.9g of 5%palladium on carbon and 1,500 ml of ethanol was stirred in a hydrogenatmosphere for 15 hours. The solid material was separated thoughfiltration, and the filtrate was concentrated. The resulting residue wasdissolved in a small amount of ethanol, and diisopropyl ether was addedthereto. The crystals precipitated were separated through filtration,and were dried to give 114.4 g of ethyl 4-acetylamino-3-aminobenzoate.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 1.27(3H, t), 2.05(3H, s), 4.23(2H, q), 5.19(2H, s),7.13(1H, d, J=8.2 Hz), 7.35(1H, s), 7.47(1H, d, J=8.2 Hz), 9.19(1H, s).

EXAMPLE 24 Synthesis of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (92)

Twenty milliliters of ethanol, 11 ml of acetic acid and 3.07 g ofreduced iron were added to 2.07 g of ethyl3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzoate, and the mixture wasrefluxed for 4 hours. The solid material was separated throughfiltration, and was washed with ethanol. The filtrate was concentrated,and a sodium hydrogencarbonate aqueous solution was added to theresidue. The mixture was extracted with ethyl acetate. The organic layerwas dried, and the solvent was then distilled off under reducedpressure. The residue was purified through silica-gel columnchromatography (eluent: a mixture of hexane and ethyl acetate at a ratioof from 100/0 to 70:30) to give 1.46 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (92).

Properties of Compound (92):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.57(3H, s), 4.37(2H, q, J=7.1Hz), 5.46(2H, s), 6.41(1H, d, J=7.8 Hz), 7.10(1H, t, J=7.8 Hz), 7.25(1H,t), 7.47(1H, d, J=8.0 Hz), 7.75(1H, d, J=8.4 Hz), 7.94(1H, s), 8.00(1H,dd, J=1.5 and 8.4 Hz).

EXAMPLE 25 Synthesis of6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole (93)

In the same manner as in Production Example 14, 1.00 g of crude ethyl3-(N-methylbutyrylamino)-4-nitrobenzoate was obtained from 1.00 g ofethyl 3-butyrylamino-4-nitrobenzoate and 0.843 g of methyl iodide.Subsequently, 0.56 g of6-ethoxycarbonyl-1-methyl-2-n-propylbenzimidazole (93) were formed inthe same manner as in Example 24.

Properties of Compound (93):

¹ H-NMR(CDCl₃, δ): 1.08(3H, t, J=7.4 Hz), 1.43(3H, t, J=7.0 Hz),1.89-1.97(2H, m), 2.89(2H, t, J=7.7 Hz), 3.79(3H, s), 4.38-4.44(2H, m),7.71(1H, d, J=8.4 Hz), 7.96(1H, dd, J=8.4 and 1.5 Hz,), 8.05(1H, d,J=1.4 Hz).

EXAMPLE 26 Synthesis of1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (94)

A solution of 1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml ofN,N-dimethylformamide was added dropwise to a slurry of 0.428 g of 60%sodium hydride and 10 ml of N,N-dimethylformamide at room temperature,and the mixture was stirred at room temperature for 30 minutes.Subsequently, a solution of 1.97 g of n-butyl iodide in 10 ml ofN,N-dimethylformamide was added dropwise thereto, and the mixture washeated at 50° C. for 13 hours. The reaction solution was poured into amixed solution of 70 g of dilute hydrochloric acid and 70 g of ethylacetate for extraction. The resulting organic layer was washed twicewith water, dried, and then concentrated under reduced pressure toobtain 2.59 g of crude ethyl 3-(N-n-butylbutyrylamino)-4-nitrobenzoate.Then, 0.81 g of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (94)were formed in the same manner as in Example 24.

Properties of Compound (94):

¹ H-NMR(CDCl₃, δ): 0.98(3H, t, J=7.4 Hz), 1.08(3H, t, J=7.4 Hz),1.43(3H, t, J=7.1 Hz), 1.75-1.83(2H, m), 1.91-1.98(2H, m), 2.88(2H, t,J=7.6 Hz), 4.15(2H, t, J=7.5 Hz), 4.42(2H, q, J=7.2 Hz), 7.73(1H, d,J=8.4 Hz), 7.96(1H, dd, J=8.5 and 1.5 Hz), 8.06(1H, d, J=1.4 Hz).

EXAMPLE 27 Synthesis of1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (95)

In the same manner as in Production Example 14, crude ethyl3-[N-(3-chlorobenzyl)butyrylamino]-4-nitrobenzoate was obtained from1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate and 1.64 g of3-chlorobenzyl bromide. This compound was converted to1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole [(95), 0.57g] in the same manner as in Example 24 without being purified.

Properties of Compound (95):

¹ H-NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.39(3H, t, J=7.1 Hz),1.85-1.92(2H, m), 2.80(2H, t, J=7.5 Hz), 4.38(2H, q, J=7.1 Hz), 5.37(2H,s), 6.86(1H, d, J=7.4 Hz), 7.04(1H, s), 7.21-7.29(2H, m), 7.77(1H, d,J=8.4 Hz), 7.96(1H, d, J=1.2 Hz), 7.99(1H, dd, J=8.5 and 1.5 Hz).

EXAMPLE 28 Synthesis of1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole (96)

In the same manner as in Production Example 14, ethyl3-(N-benzylbutyrylamino]-4-nitrobenzoate was obtained from 1.86 g ofethyl 3-butyrylamino-4-nitrobenzoate and 1.36 g of benzyl bromide. Thiscompound was converted to1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole [(96), 0.97 g] in thesame manner as in Example 24 without being purified.

Properties of Compound (96):

¹ H-NMR(CDCl₃, δ): 1.01(3H, t, J=7.4 Hz), 1.39(3H, t, J=7.1 Hz),1.83-1.91(2H, m), 2.81(2H, t, J=7.5 Hz), 4.37(2H, q, J=7.1 Hz), 5.40(2H,s), 7.03(1H, d, J=6.4 Hz), 7.28-7.33(3H, m), 7.76(1H, d, J=8.4 Hz),7.98(1H, dd, J=8.4 and 1.2 Hz), 8.00(1H, s).

EXAMPLE 29 Synthesis of1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole (97)

In the same manner as in Production Example 14, ethyl3-[N-(4-chlorobenzyl)butyrylamino]-4-nitrobenzoate was obtained from1.86 g of ethyl 3-butyrylamino-4-nitrobenzoate and 1.64 g of4-chlorobenzyl bromide. This compound was converted to1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole [(97), 1.06g] in the same manner as in Example 24 without being purified.

Properties of Compound (97):

¹ H-NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.39(3H, t, J=7.1 Hz),1.83-1.92(2H, m), 2.80(2H, t, J=7.8 Hz), 4.38(2H, q, J=7.5 Hz), 5.36(2H,s), 6.96(2H, d, J=8.2 Hz), 7.29(2H, d, J=8.3 Hz), 7.76(1H, d, J=8.4 Hz),7.96(1H, d, J=1.2 Hz), 7.99(1H, dd, J=8.3 and 1.2 Hz).

EXAMPLE 30 Synthesis of6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole(98)

In the same manner as in Example 24, 1.32 g of6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole(98) were formed from 1.82 g of ethyl4-nitro-3-[N-[2-(trifluoromethyl)benzyl]acetylamino]benzoate.

Properties of Compound (98):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.1 Hz), 2.53(3H, s), 4.37(2H, q, J=7.1Hz), 5.58(2H, s), 6.47(1H, d, J=7.7 Hz), 7.36(1H, t, J=7.5 Hz), 7.41(1H,t, J=7.5 Hz), 7.75-7.97(2H, m), 7.94(1H, d, J=1.0 Hz), 8.02(1H, dd,J=1.6 and 8.6 Hz).

EXAMPLE 31 Synthesis of6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole(99)

In the same manner as in Example 24, 1.22 g of6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole(99) were formed from 1.52 g of ethyl4-nitro-3-[N-[4-(trifluoromethyl)benzyl]acetylamino]benzoate.

Properties of Compound (99):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.58(3H, s), 4.38(2H, q, J=7.1Hz), 5.44(2H, s), 7.15(2H, d, J=8.2 Hz), 7.59(2H, d, J=8.2 Hz), 7.75(1H,d, J=8.3 Hz), 7.97(1H, s), 8.00(1H, dd, J=1.5 and 8.5 Hz).

EXAMPLE 32 Synthesis of1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (100)

In the same manner as in Production Example 14, ethyl3-[N-(3,4-dichlorobenzyl)acetylamino]-4-nitrobenzoate was obtained from1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.74 g of3,4-dichlorobenzyl bromide. This compound was converted to1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole [(100),0.76 g] in the same manner as in Example 24 without being purified.

Properties of Compound (100):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.58(3H, s), 4.39(2H, q, J=7.2Hz), 5.33(2H, s), 6.84(1H, dd, J=8.4 and 2.3 Hz), 7.16(2H, d, J=2.0 Hz),7.39(1H, d, J=8.3 Hz), 7.74(1H, d, J=8.4 Hz), 7.96(1H, d, J=1.2 Hz),8.00(1H, dd, J=8.4 and 1.5 Hz).

EXAMPLE 33 Synthesis of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (101)

In the same manner as in Production Example 14, 1.44 g of crude ethyl3-[N-biphenyl-4-ylmethyl)acetylamino]-4-nitrobenzoate were obtained from1.51 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.46 g of4-chloromethylbiphenyl. Subsequently, 1.13 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (101)were formed in the same manner as in Example 24.

Properties of Compound (101):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.62(3H, s), 4.38(2H, q, J=7.1Hz), 5.42(2H, s), 7.11(2H, d, J=8.2 Hz), 7.34(1H, m), 7.42(2H, m),7.54(4H, m), 7.74(1H, d, J=8.4 Hz), 7.99(1H, dd, J=1.5 and 8.4 Hz),8.06(1H, d, J=1.5 Hz).

EXAMPLE 34 Synthesis of6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole (102)

In the same manner as in Production Example 14, ethyl3-[N-(2-methylbenzyl)acetylamino]-4-nitrobenzoate was obtained from 1.50g of ethyl 3-acetylamino-4-nitrobenzoate and 1.65 g of 2-methylbenzylbromide. This compound was converted to6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole [(102), 0.81g] in the same manner as in Example 24 without being purified.

Properties of Compound (102):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.2 Hz), 2.43(3H, s), 2.54(3H, s),4.36(2H, q, J=7.2 Hz), 5.33(2H, s), 6.35(1H, d, J=7.7 Hz), 7.03(1H, t,J=8.2 Hz), 7.18-7.25(2H, m), 7.75(1H, d, J=8.5 Hz), 7.91(1H, d, J=1.2Hz), 7.98(1H, dd, J=8.5 and 1.5 Hz).

EXAMPLE 35 Synthesis of6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole (103)

In the same manner as in Production example 14, crude ethyl3-[N-(2-methoxybenzyl)acetylamino]-4-nitrobenzoate was obtained from1.16 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.44 g of2-methoxybenzyl chloride. Subsequently, 1.18 g of6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole (103) wereformed in the same manner as in Example 24.

Properties of Compound (103):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.2 Hz), 2.60(3H, s), 3.90(3H, s),4.37(2H, q, J=7.2 Hz), 5.36(2H, s), 6.61(1H, d, J=7.4 Hz), 6.82(1H, t,J=7.5 Hz), 6.92(1H, d, J=8.3 Hz), 7.27(1H, m), 7.71(1H, d, J=8.4 Hz),7.96(1H, dd, J=1.5 and 8.4 Hz), 8.03(1H, d, J=1.3 Hz).

EXAMPLE 36 Synthesis of6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole (104)

In the same manner as in Production Example 14, crude ethyl3-[N-(4-methoxybenzyl)acetylamino]-4-nitrobenzoate was obtained from1.60 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.49 g of4-methoxybenzyl chloride. Subsequently, 1.27 g of6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole (104) wereformed in the same manner as in Example 24.

Properties of Compound (104):

¹ H-NMR(CDCl₃,δ): 1.40(3H, t, J=7.1 Hz), 2.59(3H, s), 3.77(3H, s),4.38(2H, q, J=7.1 Hz), 5.31(2H, s), 6.84(2H, m), 7.00(2H, m), 7.71(1H,d, J=8.4 Hz), 7.97(1H, dd, J=1.4 and 8.4 Hz), 8.03(1H, d, J=1.3 Hz).

EXAMPLE 37 Synthesis of1-[2-(benzenesulfonylmethyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole(105)

In the same manner as in Production Example 14, ethyl3-[N-[2-(benzenesulfonylmethyl)benzyl]acetylamino]-4-nitrobenzoate wasobtained from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.93 gof 2-(benzenesulfonylmethyl)benzyl bromide. This compound was convertedto1-[2-benzenesulfonylmethyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole[(105), 0.89 g] in the same manner as in Example 24 without beingpurified.

Properties of Compound (105):

¹ H-NMR(CDCl₃, δ): 1.37(3H, t, J=7.1 Hz), 2.57(3H, s), 4.36(2H, q, J=7.1Hz), 4.50(2H, s), 5.60(2H, s), 6.38(1H, d, J=6.7 Hz), 6.88(1H, dd, J=1.5and 7.3 Hz), 7.10-7.18(2H, m), 7.57(2H, t, J=7.6 Hz), 7.69-7.78(2H, m),7.79(1H, dd, J=0.8 and 8.1 Hz), 7.92(1H, d, J=1.2 Hz), 7.99(1H, dd,J=1.5 and 8.4 Hz).

EXAMPLE 38 Synthesis of1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole(106)

In the same manner as in Example 24, 1.75 g of1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole(106) were formed from 3.33 g of 2-cyanobenzyl3-[N-(2-cyanobenzyl)acetylamino]-4-nitrobenzoate.

Properties of Compound (106):

¹ H-NMR(CDCl₃, δ): 2.60(3H, s), 5.55(2H, s), 5.60(2H, s), 6.68(1H, d,J=7.3 Hz), 7.41-7.48(3H, m), 7.61(2H, m), 7.72(1H, d, J=7.6 Hz),7.76(1H, d, J=7.6 Hz), 7.77(1H, d, J=8.6 Hz), 8.02(1H, s), 8.05(1H, dd,J=8.4 and 1.5 Hz).

EXAMPLE 39 Synthesis of1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (107)

In the same manner as in Production Example 14, ethyl3-[N-(biphenyl-2-ylmethyl)acetylamino]-4-nitrobenzoate was obtained from1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.47 g of2-bromomethylbiphenyl. This compound was converted to1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole [(107),1.31 g] in the same manner as in Example 24 without being purified.

Properties of Compound (107):

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=7.3 Hz), 2.39(3H, s), 4.38(2H, q, J=7.3Hz), 5.27(2H, s), 6.68(1H, d, J=7.9 Hz), 7.21(1H, dt, J=9.0 and 2.1 Hz),7.32-7.39(4H, m), 7.43(1H, dd, J=7.3 and 1.9 Hz), 7.46-7.51(2H, m),7.68(1H, d, J=8.4 Hz), 7.87(1H, d, J=1.3 Hz), 7.95(1H, dd, J=8.4 and1.5H).

EXAMPLE 40 Synthesis of 1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole(108)

In the same manner as in Production Example 14, ethyl3-(N-benzylacetylamino)-4-nitrobenzoate was obtained from 1.00 g ofethyl 3-acetylamino-4-nitrobenzoate and 1.02 g of benzyl bromide. Thiscompound was converted to1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole [(108), 0.71 g] in thesame manner as in Example 24 without being purified.

Properties of Compound (108):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.58(3H, s), 4.38(2H, q, J=7.1Hz), 5.38(2H, s), 7.05(2H, dd, J=8.3 and 1.8 Hz), 7.28-7.33(3H, m),7.72(1H, d, J=8.4 Hz), 7.98(1H, dd, J=8.4 and 1.5 Hz), 8.02(1H, d, J=1.2Hz).

EXAMPLE 41 Synthesis of1-(4-tert-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (109)

In the same manner as in Production Example 14, ethyl3-[N-(4-tert-butylbenzyl)acetylamino]-4-nitrobenzoate was obtained from1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.35 g of4-tert-butylbenzyl bromide. This compound was converted to crude1-(4-tert-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole [(109),1.60 g] in the same manner as in Example 24 without being purified.

EXAMPLE 42 Synthesis of6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole (110)

In the same manner as in Production example 14, ethyl3-[N-(2-naphthylmethyl)acetylamino]-4-nitrobenzoate was obtained from1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.32 g of2-naphthylmethyl bromide. This compound was converted to crude6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole [(110), 1.28g] in the same manner as in Example 24 without being purified.

EXAMPLE 43 Synthesis of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole (111)

In the same manner as in Production Example 14, ethyl3-[N-(biphenyl-4-ylmethyl)propionylamino]-4-nitrobenzoate was obtainedfrom 2.00 g of ethyl 4-nitro-3-propionylaminobenzoate and 2.28 g of4-chloromethylbiphenyl. This compound was converted to1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole [(111),2.07 g)] in the same manner as in Example 24 without being purified.

Properties of Compound (111):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.2 Hz), 1.45(3H, t, J=7.5 Hz),2.90(2H, q, J=7.5 Hz), 4.38(2H, q, J=7.2 Hz), 5.43(2H, s), 7.10(2H, d,J=8.3 Hz), 7.33-7.36(1H, m), 7.43(2H, t, J=7.4 Hz), 7.51-7.56(4H, m),7.79(1H, d, J=8.5 Hz), 7.80(1H, dd, J=1.5 and 8.4 Hz), 8.05(1H, d, J=1.3Hz).

EXAMPLE 44 Synthesis of1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole (112)

In the same manner as in Production Example 14, ethyl4-[N-(2-chlorobenzyl)acetylamino]-3-nitrobenzoate was obtained from 3.15g of ethyl 4-acetylamino-3-nitrobenzoate and 3.85 g of 2-chlorobenzylbromide. This compound was converted to1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole [(112), 2.54g] in the same manner as in Example 24 without being purified.

Properties of Compound (112):

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=7.1 Hz), 2.59(3H, s), 4.40(2H, q, J=7.1Hz), 5.43(1H, s), 6.43(1H, d, J=7.8 Hz), 7.10(1H, t, J=7.5 Hz), 7.19(1H,d, J=8.5 Hz), 7.25(1H, m), 7.46(1H, d, J=8.1 Hz), 7.95(1H, dd, J=1.4 and8.4 Hz), 8.47(1H, s).

EXAMPLE 45 Synthesis of1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (113)

In the same manner as in Production Example 14, ethyl3-[N-(2,6-dichlorobenzyl)acetylamino]-4-nitrobenzoate was obtained from1.50 g of ethyl 3-acetylamino-4-nitrobenzoate and 2.14 g of2,6-dichlorobenzyl bromide. This compound was converted to1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole [(113),0.91 g] in the same manner as in Example 24 without being purified.

Properties of Compound (113):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.1 Hz), 2.64(3H, s), 4.34(2H, q, J=7.1Hz), 5.61(2H, s), 7.30(1H, dd, J=7.6 and 8.5 Hz), 7.40(2H, d, J=8.0 Hz),7.66(1H, d, J=8.4 Hz), 7.87(1H, d, J=1.1 Hz), 7.91(1H, dd, J=8.4 and 1.5Hz).

EXAMPLE 46 Synthesis of6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole (114)

Two milliliters of acetic acid were added to 0.06 g of ethyl4-amino-3-(N-i-propylbutyrylamino)benzoate, and the mixture was stirredat 90° C. for 14 hours. The reaction solution was concentrated underreduced pressure to give 0.05 g of6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole (114).

Properties of Compound (114):

¹ H-NMR(CDCl₃, δ): 1.07(3H, t, J=7.4 Hz), 1.43(3H, t, J=7.0 Hz),1.69(6H, d, J=6.9 Hz), 1.85-1.92(2H, m), 2.91(2H, t, J=7.7 Hz), 4.41(2H,q, J=7.3 Hz), 4.67-4.76(1H, m), 7.72(1H, d, J=8.3 Hz), 7.94(1H, dd,J=8.7 and 1.5 Hz), 8.25(1H, d, J=1.2 Hz).

EXAMPLE 47 Synthesis of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole(115)

A solution of 0.924 g of ethyl 4-nitro-3-phenylacetylaminobenzoate in 10ml of N,N-dimethylformamide were added 0.166 g of 60% sodium hydridewhile being cooled with ice, and the mixture was stirred at roomtemperature for 1 hour. Methyl iodide (0.50 ml) was added thereto, andthe resulting mixture was stirred at room temperature for 1 hour. Thereaction solution was poured into cold 1-N hydrochloric acid, and themixture was extracted twice with ethyl acetate. The organic layer waswashed with 1-N hydrochloric acid and then with water, and was dried.The solvent was distilled off under reduced pressure. The residue waspurified through silica-gel column chromatography (developing eluent: amixture of ethyl acetate and hexane at a ratio of from 1:10 to 1:4) toobtain 0.510 g of ethyl 4-nitro-3-[N-(methyl)phenylacetylamino]benzoate.To 0.148 g of this compound were added 2 ml of ethanol, 1 ml of aceticacid and 0.240 g of reduced iron, and the mixture was refluxed for 2hours. The solid material was separated through filtration. The filtratewas concentrated, and was then purified through preparative thin-layersilica-gel chromatography (eluent: a mixture of chloroform and ethylacetate at a ratio of 2:1) to give 0.090 g of2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole (115).

Properties of Compound (115):

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=7.1 Hz), 3.63(3H, s), 4.32(2H, s),4.40(2H, q, J=7.1 Hz), 7.21-7.26(3H, m), 7.27-7.32(2H, m), 7.72(1H, d,J=8.4 Hz), 7.98(1H, dd, J=1.5 and 8.4 Hz), 8.03(1H, d, J=1.3 Hz).

EXAMPLE 48 Synthesis of1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (116)

A solution of 1.50 g of ethyl 3-acetylamido-4-nitrobenzoate in 8 ml ofN,N-dimethylformamide was added dropwise to a slurry of 0.357 g of 60%sodium hydride and 8 ml of N,N-dimethylformamide at room temperature,and the mixture was stirred for 30 minutes. Subsequently, a solution of1.74 g of 2,4-dichlorobenzyl chloride in 8 ml of N,N-dimethylformamidewas added dropwise thereto, and the mixture was stirred for 30 minutes.The reaction solution was poured into a mixed solution of 50 g of dilutehydrochloric acid and 60 g of ethyl acetate for separation. Theresulting organic layer was washed twice with 50 g of water. Thisorganic layer was concentrated under reduced pressure to obtain 3.5 g ofcrude ethyl 3-[N-(2,4-dichlorobenzyl)acetylamino]-4-nitrobenzoate. Thiscompound without being purified was dissolved in 23 ml of ethanol and 12ml of acetic acid, and then 3.32 g of reduced iron were added thereto.The mixture was heat-refluxed for 6 hours. The solid material wasremoved using a filtration aid, and the filtrate was concentrated underreduced pressure. The resulting residue was separated with the additionof 60 ml of ethyl acetate and 50 ml of dilute hydrochloric acid. Theorganic layer was washed with 50 g of a saturated aqueous solution ofsodium hydrogencarbonate and then twice with 50 g of water, and wasconcentrated under reduced pressure. The resulting residue was purifiedthrough silica-gel column chromatography (eluent: a mixture of hexaneand ethyl acetate at a ratio of from 4:1 to 1:1) to give 0.94 g of1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (116).

Properties of Compound (116):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.56(3H, s), 4.38(2H, q, J=7.1Hz), 5.41(2H, s), 6.34(1H, d, J=8.4 Hz), 7.09(1H, dd, J=8.4 and 2.0 Hz),7.49(1H, d, J=2.0 Hz), 7.75(1H, d, J=8.4 Hz), 7.92(1H, s), 8.00(1H, dd,J=8.5 and 1.4 Hz).

EXAMPLE 49 Synthesis of6-carboxy-1-(4-chlorobenzyl)-2-n-propylbenzimidazole (117)

1.06 g of 1-(4-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazolewere added 3.57 g of a 10% sodium hydroxide aqueous solution, 5 ml ofethanol and 3.57 g of water, and the mixture was heat-refluxed for 1hour. The reaction solution was adjusted to a pH of 6 with 10%hydrochloric acid, and was concentrated under reduced pressure. Ethanolwas added to the resulting residue, and the inorganic salt was separatedthrough filtration. The filtrate was concentrated under reduced pressureto obtain 0.80 g of the residue. This residue was purified throughsilica-gel column chromatography (eluent: a mixture of ethyl acetate andmethanol at a ratio of 4:1) to give 0.63 g of6-carboxy-1-(4-chlorobenzyl)-2-n-propylbenzimidazole (117).

Properties of Compound (117)

¹ H-NMR(DMSO-d6, δ): 0.96(3H, t, J=7.3 Hz), 1.76-1.88(2H, m),3.10-3.23(2H, m), 5.83(2H, s), 7.27(2H, d, J=8.4 Hz), 7.44(2H, d, J=8.4Hz), 7.89(1H, d, J=8.4 Hz), 7.89(1H, d, J=8.5 Hz), 8.28(1H, s).

EXAMPLE 50 Synthesis of 6-carboxy-1-methyl-2-n-propylbenzimidazole (118)

In the same manner as in Example 49, 0.46 g of6-carboxy-1-methyl-2-n-propylbenzimidazole (118) were formed from 0.56 gof 6-ethoxycarbonyl-1-methyl-2-n-propylcarbonylbenzimidazole.

Properties of Compound (118):

¹ H-NMR(DMSO-d6, δ): 1.00(3H, t, J=7.3 Hz), 1.79-1.93(2H, m), 3.06(3H,t, J=7.4 Hz), 3.92(3H, s), 7.76(1H, d, J=8.4 Hz), 7.97(1H, d, J=8.4 Hz),8.31(1H, s).

EXAMPLE 51 Synthesis of 6-carboxy-2-n-propyl-1-i-propylbenzimidazole(119)

In the same manner as in Example 49, 0.045 g of6-carboxy-2-n-propyl-1-i-propylbenzimidazole (119) were formed from0.045 g of 6-ethoxycarbonyl-2-n-propyl-1-i-propylbenzimidazole.

Properties of Compound (119):

¹ H-NMR(CD3OD, δ): 0.98(3H, t, J=7.4 Hz), 1.61(6H, d, J=6.9 Hz),1.74-1.82(2H, m), 2.89(2H, t, J=7.5 Hz), 3.21-3.24(2H, m), 4.78-4.83(1H,m), 7.51(1H, d, J=8.3 Hz), 7.84(1H, dd, J=8.4 and 1.5 Hz), 8.26(1H, s).

EXAMPLE 52 Synthesis of 1-n-butyl-6-carboxy-2-n-propylbenzimidazole(120)

In the same manner as in Example 49, 0.60 g of1-n-butyl-6-carboxy-2-n-propylbenzimidazole (120) were formed from 0.81g of 1-n-butyl-6-ethoxycarbonyl-2-n-propylbenzimidazole.

Properties of Compound (120):

¹ H-NMR(DMSO-d6, δ): 1.02(3H, t, J=7.3 Hz), 1.17(3H, t, J=7.3 Hz),1.33-1.41(2H, m), 1.70-1.77(2H, m), 1.85-1.93(2H, m), 3.07(2H, t, J=7.6Hz), 4.42(2H, t, J=7.4 Hz), 7.78(1H, d, J=8.5 Hz), 7.99(1H, dd, J=8.5and 1.0 Hz), 8.35(1H, s), 13.13(1H, s).

EXAMPLE 53 Synthesis of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121)

Eighty milliliters of ethanol and 37 g of a 10% sodium hydroxide aqueoussolution were added to 10.0 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and themixture was refluxed for 4 hours. The reaction solution was cooled, andwas then adjusted to a pH of 6 with 10% hydrochloric acid. Theprecipitate was collected, washed with water, and dried under reducedpressure to give 8.30 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121).

EXAMPLE 54 Synthesis of6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole (122)

In the same manner as in Example 53, 0.72 g of6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole (122) were formedfrom 0.90 g of1-(2,6-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (122):

¹ H-NMR(DMSO-d6, δ): 2.60(3H, s), 5.71(2H, s), 7.46(1H, t, J=7.9 Hz),7.57(3H, t, J=8.2 Hz), 7.73(2H, m), 12.57(1H, s).

EXAMPLE 55 Synthesis of6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole (123)

In the same manner as in Example 53, 0.98 g of6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole (123) wereformed from 1.17 g of6-ethoxycarbonyl-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole.

Properties of Compound (123):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 5.70(2H, s), 6.46-6.51(1H, m),7.51(2H, m), 7.65(1H, d, J=8.4 Hz), 7.81(1H, dd, J=1.4 and 8.4 Hz),7.82-7.87(1H, m), 7.91(1H, s).

EXAMPLE 56 Synthesis of6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole (124)

In the same manner as in Example 53, 1.07 g of6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]-benzimidazole (124)were formed from 1.22 g of6-ethoxycarbonyl-2-methyl-1-[4-(trifluoromethyl)benzyl]-benzimidazole.

Properties of Compound (124):

¹ H-NMR(DMSO-d6, δ): 2.85(3H, s), 5.92(2H, s), 7.50(2H, d, J=8.1 Hz),7.74(2H, d, J=8.1 Hz), 7.88(1H, d, J=8.5 Hz), 8.07(1H, d, J=8.5 Hz),8.31(1H, s), 13.3(1H, br s).

EXAMPLE 57 Synthesis of6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole (125)

In the same manner as in Example 53, 0.55 g of6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole (125) were formedfrom 0.76 g of1-(3,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (125):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.61(2H, s), 6.98(1H, dd, J=8.4 and1.9 Hz), 7.46(1H, d, J=1.9 Hz), 7.59(1H, d, J=8.3 Hz), 7.63(1H, d, J=8.4Hz), 7.81(1H, dd, J=8.4 and 1.4 Hz), 8.07(1H, s), 12.76(1H, s).

EXAMPLE 58 Synthesis of 1-benzyl-6-carboxy-2-n-propylbenzimidazole (126)

A 10% sodium hydroxide aqueous solution (3.61 g), 5 ml of ethanol and 3ml of water were added to 0.97 g of1-benzyl-6-ethoxycarbonyl-2-n-propylbenzimidazole, and the mixture washeat-refluxed for 1 hour. The reaction solution was adjusted to a pH of6 with 10% hydrochloric acid, and was concentrated under reducedpressure. Ethanol was added to the residue, and the inorganic salt wasseparated through filtration. The filtrate was concentrated underreduced pressure to give 0.85 g of1-benzyl-6-carboxy-2-n-propylbenzimidazole (126).

Properties of Compound (126):

¹ H-NMR(DMSO-d6, δ): 0.94(3H, t, J=7.4 Hz), 1.73-1.81(2H, m), 2.85(2H,t, J=7.3 Hz), 5.59(2H, s), 7.07(2H, dd, J=1.1 and 8.3 Hz), 7.27(1H, t,J=7.3 Hz), 7.33(2H, t, J=7.4 Hz), 7.65(1H, d, J=8.4 Hz), 7.79(1H, dd,J=1.5 and 8.4 Hz), 8.04(1H, s).

EXAMPLE 59 Synthesis of6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole (127)

In the same manner as in Example 58, 0.35 g of6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole (127) were formedfrom 0.57 g of1-(3-chlorobenzyl)-6-ethoxycarbonyl-2-n-propylbenzimidazole.

Properties of Compound (127):

¹ H-NMR(DMSO-d6, δ): 0.94(3H, t, J=7.3 Hz), 1.70-1.79(2H, m), 2.83(2H,t, J=7.4 Hz), 5.59(2H, s), 6.94(1H, s), 7.15(1H, s), 7.34(2H, d, J=4.4Hz), 7.59(1H, d, J=8.4 Hz), 7.81(1H, d, J=8.1 Hz), 8.02(1H, s).

EXAMPLE 60 Synthesis of6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (128)

In the same manner as in Example 58, 0.35 g of6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (128) were formed from0.61 g of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole.

Properties of Compound (128):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 5.96(2H, s), 6.33(1H, d, J=7.0 Hz),7.55-7.62(2H, m), 7.66(1H, d, J=8.3 Hz), 7.81(1H, d, J=8.4 Hz), 8.06(1H,s), 8.24(1H, d, J=7.0 Hz), 12.66(1H, s).

EXAMPLE 61 Synthesis of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121)

Ethanol (15 ml) and 10.6 g of a 5% sodium hydroxide aqueous solutionwere added to 1.456 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and themixture was refluxed for 1 hour. The reaction solution was cooled, andwas then adjusted to a pH of 6 with 10% hydrochloric acid. Theprecipitate was collected, washed with water, and dried under reducedpressure to give 0.645 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121).

EXAMPLE 62 Synthesis of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (129)

A 10% sodium hydroxide aqueous solution (3.10 g) and 10 ml of ethanolwere added to 0.94 g of1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole, and themixture was heat-refluxed for 1 hour. The reaction solution was adjustedto a pH of 6 with 10% hydrochloric acid. The crystals precipitated wereseparated through filtration, and were dried to give 0.68 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (129).

Properties of Compound (129):

¹ H-NMR(DMSO-d6, δ): 2.52(3H, s), 5.61(2H, s), 6.54(1H, d, J=8.4 Hz),7.33(1H, dd, J=8.4 and 2.1 Hz), 7.64(1H, d, J=8.4 Hz), 7.74(1H, d, J=2.1Hz), 7.81(1H, dd, J=8.4 and 1.5 Hz), 7.98(1H, s), 12.72(1H, s).

EXAMPLE 63 Synthesis of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole (130)

In the same manner as in Example 53, 0.83 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole (130) wereformed from 1.10 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (130):

¹ H-NMR(DMSO-d6, δ): 2.53(3H, s), 5.61(2H, s), 7.18(2H, d, J=8.2 Hz),7.34(1H, m), 7.43(2H, m), 7.62(5H, m), 7.79(1H, dd, J=1.6 and 8.5 Hz),8.09(1H, d, J=1.0 Hz), 12.72(1H, br s).

EXAMPLE 64 Synthesis of1-(4-tert-butylbenzyl)-6-carboxy-2-methylbenzimidazole (131)

In the same manner as in Example 53, 0.55 g of1-(4-tert-butylbenzyl)-6-carboxy-2-methylbenzimidazole (131) were formedfrom 1.34 g of1-(4-tert-butylbenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (131):

¹ H-NMR(DMSO-d6, δ): 1.22(9H, s), 2.57(3H, s), 5.52(2H, s), 7.03(2H, d,J=8.2 Hz), 7.35(1H, d, J=8.3 Hz), 7.60(1H, d, J=8.4 Hz), 7.78(1H, dd,J=8.4 and 1.5 Hz), 8.06(1H, s), 12.71(1H, s).

EXAMPLE 65 Synthesis of6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole (132)

In the same manner as in Example 53, 0.49 g of6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole (132) were formedfrom 0.81 g of6-ethoxycarbonyl-2-methyl-1-(2-methylbenzyl)benzimidazole.

Properties of Compound (132):

¹ H-NMR(DMSO-d6, δ): 2.41(3H, s), 2.48(3H, s), 5.55(2H, s), 6.14(1H, d,J=7.6 Hz), 7.02(1H, t, J=7.4 Hz), 7.17(1H, t, J=7.3 Hz), 7.26(1H, d,J=7.4 Hz), 7.65(1H, d, J=8.4 Hz), 7.81(1H, dd, J=8.4 and 1.4 Hz),7.97(1H, d, J=1.1 Hz), 12.71(1H, s).

EXAMPLE 66 Synthesis of6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole (133)

In the same manner as in Example 53, 1.00 g of6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole (133) was formedfrom 1.63 g of6-ethoxycarbonyl-1-(2-methoxybenzyl)-2-methylbenzimidazole.

Properties of Compound (133):

¹ H-NMR(DMSO-d6, δ): 2.55(3H, s), 3.81(3H, s), 5.42(2H, s), 6.77(1H, m),6.85(1H, m), 7.05(1H, m), 7.28(1H, m), 7.58(1H, m), 7.76(1H, m),7.99(1H, s), 12.65(1H, br s).

EXAMPLE 67 Synthesis of6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole (134)

In the same manner as in Example 53, 0.99 g of6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole (134) were formedfrom 1.27 g of6-ethoxycarbonyl-1-(4-methoxybenzyl)-2-methylbenzimidazole.

Properties of Compound (134):

¹ H-NMR(DMSO-d6, δ): 2.86(3H, s), 3.71(3H, s), 5.69(2H, s), 6.92(2H, d,J=8.4 Hz), 7.27(2H, d, J=8.4 Hz), 7.84(1H, d, J=8.5 Hz), 8.04(1H, d,J=8.5 Hz), 8.33(1H, s), 13.25(1H, br t).

EXAMPLE 68 Synthesis of6-carboxy-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]benzimidazole(135)

In the same manner as in Example 53, 0.74 g of6-carboxy-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]-benzimidazole(135) were formed from 0.89 g of6-ethoxycarbonyl-2-methyl-1-[2-(benzenesulfonylmethyl)benzyl]benzimidazole.

Properties of Compound (135):

¹ H-NMR(DMSO-d6, δ): 2.44(3H, s), 4.99(2H, s), 5.71(2H, s), 6.08(1H, d,J=6.5 Hz), 7.12-7.20(3H, m), 7.64-7.70(3H, m), 7.77-7.83(2H, m),7.89(2H, s), 7.90(1H, s), 12.71(1H, s).

EXAMPLE 69 Synthesis of6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole (136)

In the same manner as in Example 53, 1.14 g of6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole (136) were formed from2.04 g of1-(2-cyanobenzyl)-6-(2-cyanobenzyloxycarbonyl)-2-methylbenzimidazole.

Properties of Compound (136):

¹ H-NMR(DMSO-d6, δ): 2.54(3H, s), 5.80(2H, s), 6.78(1H, d, J=7.8 Hz),7.51(1H, t, J=7.4 Hz), 7.61(1H, dt, J=7.8 and 1.2 Hz), 7.64(1H, d, J=8.4Hz), 7.80(1H, dd, J=8.4 and 1.5 Hz), 7.94(1H, d, J=6.7 Hz), 8.00(1H, d,J=1.1 Hz), 12.70(1H, s).

EXAMPLE 70 Synthesis of6-carboxy-1-(biphenyl-2-ylmethyl)-2-methylbenzimidazole (137)

In the same manner as in Example 53, 1.07 g of 6-carboxy-1-(biphenyl-2-ylmethyl)-2-methylbenzimidazole (137) were formed from 1.31g of 1-(biphenyl-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (137):

¹ H-NMR(DMSO-d6, δ): 2.32(3H, s), 5.45(2H, s), 6.61(1H, d, J=7.7 Hz),7.26(1H, dt, J=7.7 and 1.4 Hz), 7.31(1H, dd, J=7.5 and 1.3 Hz), 7.36(1H,dt, J=7.5 and 0.7 Hz), 7.40-7.46(1H, m), 7.46-7.52(4H, m), 7.57(1H, d,J=8.4 Hz), 7.76(1H, dd, J=7.9 and 1.5 Hz), 7.86(1H, d, J=1.2 Hz),12.72(1H, s).

EXAMPLE 71 Synthesis of 1-benzyl-6-carboxy-2-methylbenzimidazole (138)

In the same manner as in Example 53, 0.59 g of1-benzyl-6-carboxy-2-methylbenzimidazole(138) were formed from 0.71 g of1-benzyl-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (138):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.57(2H, s), 7.11(1H, d, J=8.0 Hz),7.27(1H, t, J=7.2 Hz), 7.32-7.35(2H, m), 7.61(1H, d, J=8.3 Hz), 7.79(1H,dd, J=8.4 and 1.3 Hz), 8.06(1H, s), 12.75(1H, s).

EXAMPLE 72 Synthesis of6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole (139)

In the same manner as in Example 53, 0.80 g of6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole (139) were formedfrom 1.28 g of6-ethoxycarbonyl-2-methyl-1-(2-naphthylmethyl)benzimidazole.

Properties of Compound (139):

¹ -NMR(DMSO-d6, δ): 2.61(3H, s), 5.74(2H, s), 7.29(1H, d, J=8.6 Hz),7.46-7.52(2H, m), 7.59(1H, s), 7.63(1H, d, J=8.3 Hz), 7.78-7.92(4H, m),8.09(1H, s), 12.68(1H, s).

EXAMPLE 73 Synthesis of1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (140)

In the same manner as in Example 53, 1.70 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole (140) were formedfrom 2.07 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-ethylbenzimidazole.

Properties of Compound (140):

¹ H-NMR(DMSO-d6, δ): 1.32(3H, t, J=7.4 Hz), 2.94(2H, q, J=7.5 Hz),5.63(2H, s), 7.16(2H, d, J=8.2 Hz), 7.34(1H, t, J=7.4 Hz), 7.44(2H, t,J=7.5 Hz), 7.60-7.78(5H, m), 7.81(1H, dd, J=1.4 and 8.4 Hz), 8.10(1H, d,J=1.2 Hz), 12.73(1H, s).

EXAMPLE 74 Synthesis of5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (141)

In the same manner as in Example 53, 2.48 g of5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (141) were formedfrom 3.70 g of1-(2-chlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (141):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 5.57(2H, s), 6.53(1H, d, J=7.8 Hz),7.22(1H, t, J=7.6 Hz), 7.33(1H, t, J=7.6 Hz), 7.44(1H, d, J=8.4 Hz),7.54(1H, d, J=8.0 Hz), 7.77(1H, dd, J=1.6 and 8.5 Hz), 8.16(1H, d, J=1.3Hz), 12.71(1H, br s).

EXAMPLE 75 Synthesis of5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (142)

In the same manner as in Example 53, 0.15 g of5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole (142) were formed from0.26 g of 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole.

Properties of Compound (142):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 5.91(2H, s), 6.36(1H, dd, J=7.2 and1.8 Hz), 7.52(1H, d, J=8.5 Hz), 7.55-7.62(2H, m), 7.77(1H, dd, J=8.5 and1.5 Hz), 8.18(1H, d, J=1.3 Hz), 8.24(1H, dd, J=7.4 and 1.6 Hz),12.69(1H, s).

EXAMPLE 76 Synthesis of2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole (143)

In the same manner as in Example 53, 0.488 g of2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole (143) were formedfrom 0.635 g of2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole.

Properties of Compound (143):

¹ H-NMR(DMSO-d6, δ): 4.27(2H, s), 5.57(2H, s), 6.27(1H, d, J=7.1 Hz),7.06(1H, t), 7.10-7.29(6H, m), 7.39(1H, d, J=8.6 Hz), 7.47(1H, d, J=7.9Hz), 7.78(1H, dd, J=1.4 and 8.6 Hz), 8.21(1H, d, J=1.2 Hz), 12.71(1H, brs).

EXAMPLE 77 Synthesis of2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole (144)

In the same manner as in Example 53, 0.780 g of2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole (144) were formedfrom 1.00 g of2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole.

Properties of Compound (144):

¹ H-NMR(DMSO-d6, δ): 4.29(2H, s), 5.63(2H, s), 6.28(1H, d, J=7.8 Hz),7.07(1H, t, J=7.6 Hz), 7.15(1H, m), 7.19-7.29(5H, m), 7.49(1H, d, J=7.4Hz), 7.70(1H, d, J=8.4 Hz), 7.81(1H, d, J=8.4 Hz), 7.91(1H, s),12.73(1H, br s).

EXAMPLE 78 Synthesis of2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)benzimidazole (145)

In the same manner as in Example 53, 0.40 g of2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)benzimidazole (145) were formedfrom 0.50 g of2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole.

Properties of Compound (145):

¹ H-NMR(DMSO-d6, δ): 4.28(2H, s), 5.55(2H, s), 6.19(1H, d, J=8.4 Hz),7.08-7.22(6H, m), 7.41(1H, d, J=8.4 Hz), 7.62(1H, d, J=2.2 Hz), 7.79(1H,dd, J=1.5 and 8.6 Hz), 8.22(1H, s), 12.72(1H, br s).

EXAMPLE 79 Synthesis of2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole (146)

In the same manner as in Example 53, 0.35 g of2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole (146) were formedfrom 0.48 g of2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole.

Properties of Compound (146):

¹ H-NMR(DMSO-d6, δ): 4.30(2H, s), 5.61(2H, s), 6.19(1H, d, J=8.4 Hz),7.09-7.22(6H, m), 7.64(1H, d, J=2.1 Hz), 7.71(1H, d, J=8.4 Hz), 7.82(1H,dd, J=1.5 and 8.4 Hz), 7.94(1H, d, J=1.2 Hz), 12.78(1H, br s).

EXAMPLE 80 Synthesis of1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole (147)

In the same manner as in Example 53, 0.483 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole (147)were formed from 0.690 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole.

Properties of Compound (147):

¹ H-NMR(DMSO-d6, δ): 5.87(2H, s), 7.18(2H, d, J=8.2 Hz), 7.35(1H, t,J=7.4 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.67(4H, m), 7.98(2H, d, J=0.7Hz), 8.32(1H, s), 13.15(1H, s).

EXAMPLE 81 Synthesis of1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole (148)

In the same manner as in Example 53, 0.270 g of1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole (148)were formed from 0.38 g of1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole.

Properties of Compound (148):

¹ H-NMR(DMSO-d6, δ): 5.80(2H, s), 7.19(2H, d, J=6.3 Hz), 7.35(1H, t,J=7.2 Hz), 7.43(2H, t, J=7.3 Hz), 7.82(1H, d, J=8.7 Hz), 8.04(1H, d,J=8.7 Hz), 8.45(1H, s).

EXAMPLE 82 Synthesis of 5-ethoxycarbonyl-2-methylbenzimidazole (149)

Reduced iron (6.46 g), 48 ml of ethanol and 24 ml of acetic acid wereadded to 3.00 g of ethyl 3-acetylamino-4-nitrobenzoate, and the mixturewas heat-refluxed for 12 hours. The solid material was removed using afiltration aid, and the filtrate was concentrated under reducedpressure. To the residue were added 100 ml of ethanol and 5.2 g of 35%hydrochloric acid, and the mixture was heat-refluxed for 5 hours. Thereaction solution was neutralized with 6.3 g of sodiumhydrogencarbonate, and was filtrated. The filtrate was concentratedunder reduced pressure. The residue was separated with the addition of70 ml of ethyl acetate and 70 ml of water. The organic layer was washedthree times with water, and the aqueous layer was extracted three timeswith ethyl acetate. The resulting organic layer was concentrated underreduced pressure to give 1.53 g of a powder of5-ethoxycarbonyl-2-methylbenzimidazole (149).

Properties of Compound (149):

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=6.9 Hz), 2.67(3H, s), 4.40(2H, q, J=7.1Hz), 7.55(1H, d, J=8.4 Hz), 7.96(1H, dd, J=8.4 and 1.5 Hz), 8.27(1H, d,J=1.4 Hz).

EXAMPLE 83 Synthesis of 2-benzyl-5-ethoxycarbonylbenzimidazole (150)

A mixture of 3.60 g of ethyl 3-nitro-4-phenylacetylaminobenzoate, 47 mlof ethanol, 23 ml of acetic acid and 6.4 g of reduced iron washeat-refluxed for 4 hours. The solid material was separated throughfiltration, and the filtrate was concentrated. To the residue were added50 ml of ethanol and 5 g of 35% hydrochloric acid. The mixture wasstirred for 40 hours while being heat-refluxed. The reaction solutionwas neutralized with sodium hydrogencarbonate, and was extracted withchloroform. The organic layer was concentrated under reduced pressure,and was purified through silica-gel column chromatography to give 2.30 gof 2-benzyl-5-ethoxycarbonylbenzimidazole (150).

Properties of Compound (150):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 4.26(2H, s), 4.37(2H, q, J=7.1Hz), 7.22-7.36(5H, m), 7.50(1H, d, J=8.6 Hz), 7.94(1H, dd, J=1.5 and 8.6Hz), 8.23(1H, d, J=1.3 Hz).

EXAMPLES 84 AND 85 Synthesis of6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (151) and5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (152)

To 1.00 g of 5-ethoxycarbonyl-2-methylbenzimidazole were added 15 ml ofN,N-dimethylformamide, 1.59 g of 2-nitrobenzyl bromide and 1.23 g ofsodium hydrogencarbonate, and the mixture was heated at 60° C. for 1hour. The reaction solution was separated with the addition of 70 ml ofethyl acetate and 70 ml of water. The organic layer was then washedthree times with water, and the aqueous layer was extracted three timeswith ethyl acetate. The resulting organic layer was concentrated underreduced pressure to obtain a mixture of6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole and5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole. The mixturewas purified through medium-pressure silica-gel column chromatography(eluent: a mixture of hexane and ethyl acetate at a ratio of from 1:4 to0:100) to give 0.614 g of6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (151) and 0.259g of 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (152).

Properties of Compound (151):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.2 Hz), 2.56(3H, s), 4.37(2H, q, J=7.1Hz), 5.84(2H, s), 6.41(1H, d, J=6.8 Hz), 7.44-7.53(2H, m), 7.78(1H, d,J=8.6 Hz), 7.88(1H, s), 8.02(1H, dd, J=8.3 and 1.5 Hz), 8.30(1H, dd,J=7.9 and 1.5 Hz).

Properties of Compound (152):

¹ H-NMR(CDCl₃, δ): 1.42(3H, t, J=7.0 Hz), 2.56(3H, s), 4.40(2H, q, J=7.0Hz), 5.80(2H, s), 6.43(1H, dd, J=7.6 and 1.0 Hz), 7.14(1H, d, J=8.3 Hz),7.45-7.53(2H, m), 7.95(1H, dd, J=8.4 and 1.5 Hz), 8.27(1H, dd, J=8.0 and1.7 Hz), 8.48(1H, d, J=1.2 Hz).

EXAMPLES 86 AND 87 Synthesis of2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole (153) and2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole (154)

In the same manner as in Examples 84 and 85, 1.06 g of2-benzyl-1-(2-chlorobenzyl)-6-ethoxycarbonylbenzimidazole (153) and0.640 g of 2-benzyl-1-(2-chlorobenzyl)-5-ethoxycarbonylbenzimidazole(154) were formed from 2.37 g of 2-benzyl-5-ethoxycarbonylbenzimidazoleand 3.94 g of 2-chlorobenzyl bromide.

Properties of Compound (153):

¹ H-NMR(CDCl₃, δ): 1.83(3H, t, J=7.1 Hz), 4.23(2H, s), 4.35(2H, q, J=7.1Hz), 5.36(2H, s), 6.23(1H, d, J=7.8 Hz), 6.97(1H, t, J=7.6 Hz),7.11-7.45(7H, m), 7.85(1H, d, J=8.5 Hz), 7.91(1H, s), 8.02(1H, dd, J=1.2and 8.6 Hz).

Properties of Compound (154):

¹ H-NMR(CDCl₃, δ): 1.41(3H, t, J=7.1 Hz), 4.25(2H, s), 4.41(2H, q, J=7.1Hz), 5.33(2H, s), 6.22(1H, d, J=6.9 Hz), 6.97(1H, t, J=7.6 Hz),7.12-7.28(7H, m), 7.40(1H, d, J=8.0 Hz), 7.95(1H, dd, J=1.6 and 8.6 Hz),8.60(1H, d, J=1.4 Hz).

EXAMPLES 88 AND 89 Synthesis of2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonylbenzimidazole (155) and2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole (156)

In the same manner as in Examples 84 and 85, 0.49 g of2-benzyl-1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-benzimidazole and 0.52g of 2-benzyl-1-(2,4-dichlorobenzyl)-5-ethoxycarbonylbenzimidazole (156)were formed from 2.37 g of 2-benzyl-5-ethoxycarbonyl-benzimidazole and4.45 g of 2,4-dichlorobenzyl bromide.

Properties of Compound (155):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t), 4.24(2H, s), 4.37(2H, q), 5.32(2H, s),6.08(1H, d, J=8.3 Hz), 6.90(1H, d, J=8.4 Hz), 7.12-7.24(5H, m), 7.41(1H,s), 7.84(1H, d, J=8.4 Hz), 7.88(1H, s), 8.03(1H, d, J=8.4 Hz).

Properties of Compound (156):

¹ H-NMR(CDCl₃, δ): 1.42(3H, t, J=7.1 Hz), 4.25(2H, s), 4.41(2H, q, J=7.1Hz), 5.28(2H, s), 6.07(1H, d, J=8.4 Hz), 6.90(1H, dd, J=1.9 and 8.4 Hz),7.08-7.28(6H, m), 7.40(1H, d, J=2.1 Hz), 7.96(1H, dd, J=1.3 and 8.3 Hz),8.56(1H, d, J=0.9 Hz).

EXAMPLE 90 Synthesis of 5-ethoxycarbonyl-2-trifluoromethylbenzimidazole(157)

Five-percent palladium on carbon (0.50 g) was added to a solution of4.00 g of ethyl 3-amino-4-nitro-benzoate in 100 ml of methanol, and themixture was stirred in a hydrogen atmosphere at 50° C. for 16 hours. Thesolid material was separated through filtration, and the filtrate wasconcentrated to obtain ethyl 3,4-diaminobenzoate. Twenty milliliters oftrifluoroacetic acid were added thereto, and the mixture was stirred at60° C. for 2 hours. The reaction solution was concentrated, andchloroform was added thereto. The crystals precipitated were separatedthrough filtration, and were dried to give 4.46 g of5-ethoxycarbonyl-2-trifluoromethylbenzimidazole (157).

Properties of Compound (157):

¹ H-NMR(DMSO-d6, δ): 1.36(3H, t, J=7.0 Hz), 4.36(2H, q, J=7.0 Hz),7.82(1H, d, J=8.5 Hz), 7.99(1H, dd, J=1.5 and 8.7 Hz), 8.33(1H, s).

EXAMPLES 91 AND 92 Synthesis of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole(158) and1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole(159)

In the same manner as in Examples 84 and 85, 0.69 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-trifluoromethylbenzimidazole(158) and 0.38 g of1-(biphenyl-4-ylmethyl)-5-ethoxycarbonyl-2-trifluoromethylbenzimidazole(159) were formed from 2.00 g of5-ethoxycarbonyl-2-trifluoromethylbenzimidazole and 10.08 g of4-bromomethylbiphenyl.

Properties of Compound (158):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t), 4.38(2H, q), 5.64(2H, s), 7.18(2H, d,J=8.2 Hz), 7.34(1H, t, J=7.4 Hz), 7.42(2H, t, J=7.4 Hz), 7.52-7.57(4H,m), 7.95(1H, d, J=8.8 Hz), 8.09(2H, dd, J=1.4 and 8.8 Hz), 8.14(1H, d,J=1.1 Hz).

Properties of Compound (159):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t), 4.40(2H, q), 5.59(2H, s), 7.16(2H, d,J=8.1 Hz), 7.34(2H, t, J=6.2 Hz), 7.41(2H, t, J=7.5 Hz), 7.53(4H, m),8.08(1H, dd, J=1.3 and 9.1 Hz), 8.65(1H, s).

PRODUCTION EXAMPLE 38 Production of1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole

A solution of 2.66 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole in 20 ml oftetrahydrofuran was slowly added to a solution of 1.54 g of lithiumaluminum hydride in 20 ml of tetrahydrofuran at a temperature of from 20to 25° C. Further, the mixture was stirred at room temperature for 1hour. Thirty milliliters of tetrahydrofuran were added thereto to dilutethe reaction solution. Lithium ammonium hydride was decomposed andsolidified with a saturated aqueous solution of sodium sulfate, and thetetrahydrofuran layer was separated. The solvent was distilled off, andthe residue was purified through silica-gel column chromatography(eluent: a mixture of chloroform and methanol at a ratio of 9:1) to give1.45 g of 1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.53(3H, s), 4.77(2H, s), 5.39(2H, s), 6.40(1H, d,J=7.7 Hz), 7.08(1H, t, J=7.7 Hz), 7.20-7.28(3H, m), 7.45(1H, d, J=7.9Hz), 7.70(1H, d, JH=8.2 Hz).

PRODUCTION EXAMPLE 39 Production of1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole

In the same manner as in Production Example 38, 3.72 g of1-(biphenyl-4-ylmethyl)-6-hydroxymethyl-2-methylbenzimidazole wereformed from 5.30 g of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 2.17g of lithium aluminum hydride.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.78(2H, s), 5.37(2H, s), 7.11(2H, d,J=8.3 Hz), 7.24(1H, d, J=8.3 Hz), 7.30-7.37(2H, m), 7.42(2H, t),7.51-7.56(4H, m), 7.70(1H, d, J=8.2 Hz).

PRODUCTION EXAMPLE 40 Production of1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride

Five milliliters of thionyl chloride were added to 3.56 g of1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole, and themixture was stirred at room temperature for 20 minutes and then at 80°C. for 20 minutes. After excess thionyl chloride was distilled off underreduced pressure, the residue was dissolved in 10 ml of chloroform, andthe solution was crystallized from hexane. The crystals were separatedthrough filtration, washed with hexane, and dried to give 4.07 g of1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloride.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 3.01(3H, s), 4.68(2H, s), 5.61(2H, s), 6.71(1H, d,J=7.5 Hz), 7.24-7.29(1H, m), 7.38(1H, t, J=7.7 Hz), 7.44(1H, s),7.52(2H, d, J=8.2 Hz), 7.92(1H, d, J=8.4 Hz).

PRODUCTION EXAMPLE 41 Production of1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole

Two milliliters of thionyl chloride were added to a solution of 3.62 gof 1-(biphenyl-4-ylmethyl)-6-hydoroxymethyl-2-methylbenzimidazole in 30ml of chloroform at room temperature, and the mixture was stirred at 60°C. for 1 hour. A sodium hydrogencarbonate aqueous solution was addedthereto to stop the reaction. The chloroform layer was washed withwater, and was dried. The solvent was distilled off under reducedpressure, and the residue was crystallized from ethyl acetate. Thecrystals were separated through filtration, washed with ethyl acetate,and then dried to give 2.04 g of1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.67(3H, s), 4.71(2H, s), 5.40(2H, s), 7.12(2H, d,J=8.2 Hz), 7.31-7.38(3H, m), 7.43(2H, t), 7.52-7.58(4H, m), 7.75(1H, d,J=8.2 Hz).

PRODUCTION EXAMPLE 42 Production of1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole

Manganese dioxide (3.46 g) was added to a solution of 3.46 g of1-(2-chlorobenzyl)-6-hydroxymethyl-2-methylbenzimidazole in 100 ml oftoluene, and toluene was heat-refluxed for 3.5 hours while the mixturewas dehydrated using a molecular sieve 4A. The solid material wasseparated through filtration, and was washed with chloroform. Thefiltrate was concentrated to give 3.35 g of1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.61(3H, s), 5.48(2H, s), 6.42(1H, d, J=7.8 Hz),7.11(1H, t, J=7.6 Hz), 7.27(1H, t), 7.48(1H, d, J=8.0 Hz), 7.76(1H, s),7.81(1H, dd, J=1.4 and 8.3 Hz), 7.86(1H, d, J=8.3 Hz), 10.02(1H, s).

IR(KBr): 1676 cm⁻¹.

mp: 124.1-125.2° C.

PRODUCTION EXAMPLE 43 Production of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile

Potassium cyanate (0.450 g) and 0.450 g of 18-crown-6 were added to asolution of 1.20 g of1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole in 10 ml ofdimethylsulfoxide, and the mixture was stirred at room temperature for18 hours. The reaction mixture was extracted with the addition ofchloroform, water and a small amount of aqueous ammonia. The organiclayer was concentrated, and the residue was purified through silica-gelcolumn chromatography (eluent: a mixture of chloroform and methanol at aratio of 20:1) to give 0.500 g of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.52(3H, s), 3.80(2H, s), 5.37(2H, s), 6.40(1H, d,J=7.6 Hz), 7.09(1H, t), 7.10-7.19(2H, m), 7.23(1H, t), 7.44(1H, d, J=7.9Hz), 7.70(1H, d, J=8.2 Hz).

PRODUCTION EXAMPLE 44 Production of6-carboxy-1-(2-chlorobenzyl)benzimidazole

To 0.490 g of 4-amino-3-(2-chlorobenzyl)aminobenzoic acid formed by themethod described in U.S. Pat. No. 5,294,631 were added 0.5 ml of 98%formic acid, and the mixture was refluxed for 1 hour. The solid materialprecipitated was collected, washed with water, and dried to give 0.468 gof 6-carboxy-1-(2-chlorobenzyl)benzimidazole.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 5.69(2H, s), 7.02(1H, dd, J=1.5 and 7.7 Hz),7.30(1H, t, J=7.5 Hz), 7.36(1H, dt, J=1.7 and 7.5 Hz), 7.53(1H, dd,J=1.3 and 7.9 Hz), 7.75(1H, d, J=8.4 Hz), 7.83(1H, dd, J=1.5 and 8.4Hz), 8.09(1H, s), 8.54(1H, s), 12.8(1H, br s).

EXAMPLE 93 Synthesis of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (92)

One-hundred grams of 2-chlorobenzyl bromide were added to a solution of86.0 g of ethyl 4-acetylamino-3-aminobenzoate and 37.3 g of potassiumcarbonate in 750 ml of ethanol, and the mixture was stirred at 60° C.for 14 hours. The solid material was separated through filtration, andthe filtrate was concentrated to 500 ml under reduced pressure. Then,38.7 g of 35% hydrochloric acid were added thereto, and the mixture wasstirred at 60° C. for 2 hours. The solid material was separated throughfiltration, and the residue was neutralized with sodiumhydrogencarbonate. Ethanol was distilled off under reduced pressure. Theresidue was extracted three times with ethyl acetate and with water. Theorganic layer was washed with water, and was dried. The solvent wasdistilled off until the amount of the organic layer reached 300 ml. Thecrystals precipitated were separated through filtration, and wererecrystallized from ethanol to obtain 54.3 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole(192). Thefiltrate was also all collected, and was concentrated. The resultingcrystals were recrystallized from ethanol to give 18.1 g of1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (92).

Properties of Compound (92):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.57(3H, s), 4.37(2H, q, J=7.1Hz), 5.46(2H, s), 6.41(1H, d, J=7.8 Hz), 7.10(1H, t, J=7.8 Hz), 7.25(1H,t), 7.47(1H, d, J=8.0 Hz), 7.75(1H, d, J=8.4 Hz), 7.94(1H, s), 8.00(1H,dd, J=1.5 and 8.4 Hz).

mp: 126.0-127.0° C.

EXAMPLE 94 Synthesis of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121)

To 60.0 g of 1-(2-chlorobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazolewere added 240 g of a 10% sodium hydroxide aqueous solution and 200 mlof ethanol, and the mixture was heat-refluxed for 2 hours. The reactionsolution was cooled, and was then adjusted to a pH of 6 with 10%hydrochloric acid. The crystals precipitated were separated throughfiltration, and were dried to give 54.7 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole (121).

Properties of Compound (121):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 5.62(2H, s), 6.54(1H, d, J=7.7 Hz),7.23(1H, t, J=7.5 Hz), 7.33(1H, t, J=7.7 Hz), 7.55(1H, d, J=8.0 Hz),7.63(1H, d, J=8.4 Hz), 7.79(1H, d, J=8.4 Hz), 7.95(1H, s).

mp: 300.8-303.0° C.

EXAMPLE 95 Synthesis of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (160)

To 0.500 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrilewas added 10% hydrochloric acid, and the mixture was heat-refluxed for15 hours. The reaction mixture was neutralized with a saturated aqueoussolution of sodium hydrogencarbonate, and was extracted with chloroform.The organic layer was concentrated, and was purified through silica-gelcolumn chromatography (eluent: a mixture of chloroform and methanol at aratio of 9:1 to 4:1) to give 0.170 g of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid (160).

Properties of Compound (160):

¹ H-NMR(CDCl₃, δ): 2.42(3H, s), 3.56(2H, s), 5.15(2H, s), 6.33(1H, d),6.96(1H, t), 7.03(1H, s), 7.13(2H, m), 7.35(1H, d, J=7.9 Hz), 7.62(1H,d), 8.90(1H, br s).

EXAMPLE 96 Synthesis of methyl1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylate

Methyl trifluorophosphoranilacetate (4.49 g) was added to a solution of2.73 g of 1-(2-chlorobenzyl)-6-formyl-2-methylbenzimidazole in 50 ml of1,4-dioxane, and the mixture was stirred for 6 hours while beingheat-refluxed. After the reaction solution was cooled, the solvent wasdistilled off under reduced pressure, and the residue was purifiedthrough silica-gel chromatography (eluent: a mixture of chloroform andmethanol at a ratio of 9:1) to obtain 7.43 g of crude methyl1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylate (161). This crudeproduct was used in the subsequent reaction at once.

EXAMPLE 97 Synthesis of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid

The above-mentioned crude methyl1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylate (3.29 g) wasdissolved in 20 ml of ethanol, and 10.1 g of a 5% sodium hydroxideaqueous solution were added thereto. The mixture was refluxed for 2hours. The reaction solution was neutralized with a hydrochloric acidaqueous solution. The solvent was distilled off under reduced pressure,and the residue was purified through silica-gel chromatography (eluent:a mixture of chloroform and methanol at a ratio of from 9:1 to 6:1) togive 1.10 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid.

Properties of Compound (162):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.65(2H, s), 6.54(1H, d, J=15.9 Hz),6.62(1H, d, J=7.6 Hz), 7.25(1H, t), 7.35(1H, t), 7.56(1H, d, J=8.1 Hz),7.60-7.70(3H, m), 7.99(1H, s), 12.35(1H, br s).

EXAMPLE 98 Synthesis of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163)

N,N'-carbonyldiimidazole (45.8 g) was added at a time to a solution of45.0 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 950 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, 47.1 g of benzenesulfonamide and35.0 g of diazabicycloundecene were added thereto, and the mixture wasstirred at 100° C. for 70 hours. The reaction solution was cooled, andthe solvent was distilled off under reduced pressure. To the residuewere added 300 ml of water and 200 ml of methanol. Further, 60.7 g of35% hydrochloric acid were added thereto to adjust the solution to a pHof 5.5. The crystals precipitated were separated through filtration,washed with 200 ml of a mixed solution of methanol and water (at a ratioof 1:1), and dried to obtain 38.4 g of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole.Water was added to the filtrate. The crystals precipitated wereseparated through filtration, washed with water, and dried. The amountof the crystals was 13.3 g. The crystals were combined, and weredissolved by being heated with the addition of 3300 ml of acetone and900 ml of water. From this solution, 200 ml of the solvent weredistilled off while being heated, and the residue was cooled. Thecrystals precipitated were separated through filtration, and were driedto give 33.8 g of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163).

Properties of Compound (163):

¹ H-NMR(DMSO-d6, δ): 2.53(3H, s), 5.46(2H, s), 6.34(1H, d, J=7.8 Hz),7.11(1H, m), 7.27(1H, m), 7.48(1H, m), 7.52(2H, m), 7.60(1H, m),7.69(1H,d, J=8.6 Hz), 7.90(1H, m), 8.09(2H, m), 8.11(1H, s), 11.84(1H,br s).

IR(KBr): 1684, 1448 cm⁻¹.

Mass(FAB): m/e 440(M+1).

mp: 273.5-274.3° C.

EXAMPLE 99 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole(164)

In the same manner as in Example 98, 0.473 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole(164) were formed from 0.600 g of1-(biphenyl-4-ylmethyl)-2-ethyl-6-carboxybenzimidazole, 0.546 g ofN,N'-carbonyldiimidazole, 0.529 g of benzenesulfonamide and 0.512 g ofdiazabicycloundecene.

Properties of Compound (164):

¹ H-NMR(DMSO-d6, δ): 1.29(3H, t, J=7.4 Hz), 2.88(2H, q, J=7.4 Hz),5.59(2H, s), 7.16(2H, d, J=8.2 Hz), 7.33-7.37(1H, m), 7.44(2H, t, J=7.5Hz), 7.59-7.71(8H, m), 7.74(1H, dd, J=8.4 and 1.4 Hz), 7.98-8.02(2H, m),8.21(1H, s), 12.43(1H, s).

IR(KBr): 1684 cm⁻¹.

mp: 149.5-157.0° C.

EXAMPLE 100 Synthesis of5-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(165)

In the same manner as in Example 98, 0.480 g of5-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(165) were formed from 0.450 g of5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g ofN,N'-carbonyldiimidazole, 0.470 g of benzenesulfonamide and 0.456 g ofdiazabicycloundecene.

Properties of Compound (165):

¹ H-NMR(DMSO-d6, δ): 2.53(3H, s), 5.61(2H, s), 6.57(1H, d, J=7.4 Hz),7.22(1H, t), 7.33(1H, t), 7.50(1H, d, J=8.6 Hz), 7.54(1H, dd, J=7.9 and0.9 Hz), 7.63(2H, t), 7.71(2H, m), 8.00(2H, d, J=7.3 Hz), 8.21(1H, d,J=1.4 Hz), 12.50(1H, br s).

IR(KBr): 1685 cm⁻¹.

mp: 137.0-138.5° C.

EXAMPLE 101 Synthesis of5-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(166)

In the same manner as in Example 98, 0.520 g of5-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(166) were formed from 0.450 g of5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g ofN,N'-carbonyldiimidazole, 0.573 g of 4-chlorobenzenesulfonamide and0.456 g of diazabicycloundecene.

Properties of Compound (166):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 5.58(2H, s), 6.51(1H, d, J=7.6 Hz),7.21(1H, t), 7.32(1H, t), 7.45(1H, d, J=8.6 Hz), 7.53(1H, d, J=7.8 Hz),7.69(3H, d, J=8.6 Hz), 7.99(2H, d, J=8.6 Hz), 8.18(1H, s), 12.58(1H, brs).

IR(KBr): 1619 cm⁻¹.

mp: 261.5-263.0° C.

EXAMPLE 102 Synthesis of1-(2-chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)benzimidazole(167)

In the same manner as in Example 98, 0.352 g of1-(2-chlorobenzyl)-2-methyl-5-(2-naphthalenesulfonylcarbamoyl)benzimidazole(167) were formed from 0.450 g of5-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g ofN,N'-carbonyldiimidazole, 0.620 g of 2-naphthalenesulfonamide and 0.456g of diazabicycloundecene.

Properties of Compound (167):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 5.56(2H, s), 6.49(1H, d, J=7.7 Hz),7.20(1H, t, J=7.6 Hz), 7.31(1H, t, J=7.7 Hz), 7.44(1H, d, J=8.6 Hz),7.52(1H, d, J=8.0 Hz), 7.66-7.75(3H, m), 7.97(1H, d, J=8.8 Hz), 8.04(1H,d, J=8.0 Hz), 8.14(1H, d, J=8.8 Hz), 8.19(1H, s), 8.23(1H, d, J=8.0 Hz),8.68(1H, s), 12.55(1H, br s).

IR(KBr): 1685 cm⁻¹.

mp: 236.5-238.0° C.

EXAMPLE 103 Synthesis of1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-methylbenzimidazole(168)

In the same manner as in Example 98, 0.564 g of1-(2-chlorobenzyl)-6-methanesulfonylcarbamoyl-2-methylbenzimidazole(168) were formed from 0.500 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.539 g ofN,N'-carbonyldiimidazole, 0.316 g of methanesulfonamide and 0.506 g ofdiazabicycloundecene.

Properties of Compound (168):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 3.35(3H, s), 5.60(2H, s), 6.43(1H, d,J=7.8 Hz), 7.23(1H, t), 7.34(1H, t, J=7.7 Hz), 7.57(1H, d, J=8.0 Hz),7.68(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.7 and 8.5 Hz), 8.13(1H, d, J=1.5Hz), 11.94(1H, br s).

IR(KBr): 1670 cm⁻¹.

mp: 302.0-303.0° C.

EXAMPLE 104 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(169)

In the same manner as in Example 98, 0.595 g of6-(1-butanesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(169) were formed from 0.500 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.539 g ofN,N'-carbonyldiimidazole, 0.456 g of 1-butanesulfonamide and 0.506 g ofdiazabicycloundecene.

Properties of Compound (169):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.4 Hz), 1.38(2H, m), 1.65(2H, m),2.49(3H, s), 3.49(2H, m), 5.60(2H, s), 6.44(1H, d, J=7.6 Hz), 7.23(1H,t, J=7.6 Hz), 7.35(1H, t), 7.56(1H, d, J=8.0 Hz), 7.68(1H, d, J=8.4 Hz),7.80(1H, dd, J=1.6 and 8.4 Hz), 8.11(1H, d, J=1.4 Hz), 11.86(1H, br s).

IR(KBr): 1684 cm⁻¹.

mp: 214.0-217.0° C.

EXAMPLE 105 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(1-octanesulfonylcarbamoyl)benzimidazole(170)

In the same manner as in Example 98, 0.309 g of1-(2-chlorobenzyl)-2-methyl-6-(1-octanesulfonylcarbamoyl)benzimidazole(170) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 406 g of 1-octanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (170):

¹ H-NMR(DMSO-d6, δ): 0.82(3H, t, J=7.3 Hz), 1.13-1.28(8H, m),1.32-1.41(2H, m), 1.62-1.71(2H, m), 2.50(3H, s), 3.50(2H, t, J=8.5 Hz),5.61(2H, s), 6.45(1H, d, J=7.7 Hz), 7.24(1H, t, J=7.5 Hz), 7.35(1H, t,J=7.5 Hz), 7.58(1H, d, J=8.0 Hz), 7.69(1H, d, J=8.4 Hz), 7.81(1H, d,J=8.5 Hz), 8.12(1H, s), 11.86(1H ,s).

IR(KBr): 1674 cm⁻¹.

mp: 180.0-183.0° C.

EXAMPLE 106 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(2-propanesulfonylcarbamoyl)benzimidazole(171)

In the same manner as in Example 98, 0.417 g of1-(2-chlorobenzyl)-2-methyl-6-(2-propanesulfonylcarbamoyl)benzimidazole(171) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.328 g of 2-propanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (171):

¹ H-NMR(DMSO-d6, δ): 1.30(6H, d, J=6.9 Hz), 2.50(3H, s), 3.81-3.87(1H,m), 5.62(2H, s), 6.46(1H, d, J=7.7 Hz), 7.25(1H, t, J=7.5 Hz), 7.35(1H,t, J=7.5 Hz), 7.62(1H, d, J=7.9 Hz), 7.69(1H, d, J=8.5 Hz), 7.81(1H, d,J=8.6 Hz), 8.12(1H, s), 11.83(1H, s).

IR(KBr): 1670 cm⁻¹.

mp: 215.0-217.5° C.

EXAMPLE 107 Synthesis of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(172)

In the same manner as in Example 98, 0.349 g of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(172) were formed from 0.300 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole, 0.323 g ofN,N'-carbonyldiimidazole, 0.273 g of 1-butanesulfonamide and 0.303 g ofdiazabicycloundecene.

Properties of Compound (172)

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.4 Hz), 1.36-1.43(2H, m),1.63-1.72(2H, m), 2.57(3H, s), 3.52(2H, t, J=7.7 Hz), 5.60(2H, s),7.21(2H, d, J=8.2 Hz), 7.35(1H, t, J=7.3 Hz), 7.44(2H, t, J=7.5 Hz),7.60-7.68(5H, m), 7.81(1H, dd, J=1.6 and 8.4 Hz), 8.26(1H, d, J=1.4 Hz),11.97(1H, s).

IR(KBr): 1676 cm⁻¹.

mp: 219.5-222.5° C.

EXAMPLE 108 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(173)

In the same manner as in Example 98, 0.459 g of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(173) were formed from 0.400 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.364 g of 1-butanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (173):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.3 Hz), 1.36-1.42(2H, m),1.63-1.70(2H, m), 2.50(3H, s), 3.51(2H, t, J=7.7 Hz), 5.59(2H, s),6.45(1H, d, J=8.4 Hz), 7.33(1H, dd, J=2.1 and 8.4 Hz), 7.69(1H, d, J=8.4Hz), 7.76(1H, d, J=2.0 Hz), 7.81(1H, dd, J=1.7 and 8.5 Hz), 8.11(1H, d,J=1.3 Hz), 11.90(1H, s).

IR(KBr): 1670 cm⁻¹.

mp: 222.0-223.0° C.

EXAMPLE 109 Synthesis of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole(174)

In the same manner as in Example 98, 0.300 g of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole(174) were formed from 0.300 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.340 g ofN,N'-carbonyldiimidazole, 0.300 g of butanesulfonamide and 0.320 g ofdiazabicycloundecene.

Properties of Compound (174):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.3 Hz), 1.30(3H, t, J=7.5 Hz),1.35-1.44(2H, m), 1.64-1.72(2H, m), 2.90(2H, q, J=7.4 Hz), 3.52(2H, t,J=7.7 Hz), 5.61(2H, s), 7.19(2H, d, J=8.3 Hz), 7.35(1H, t, J=7.3 Hz),7.44(2H, t, J=7.5 Hz), 7.61-7.67(4H, m), 7.71(1H, d, J=8.5 Hz), 7.82(1H,dd, J=1.6 and 8.5 Hz), 8.27(1H, d, J=1.3 Hz), 12.01(1H, s). IR(Nujol):1687,1682 cm⁻¹.

mp: 171.8-173.0° C.

EXAMPLE 110 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole(175)

In the same manner as in Example 98, 0.508 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole(175) were formed from 0.483 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-trifluoromethylbenzimidazole, 0.396g of N,N'-carbonyldiimidazole, 0.383 g of benzenesulfonamide and 0.371 gof diazabicycloundecene.

Properties of Compound (175):

¹ H-NMR(DMSO-d6, δ): 5.81(2H, s), 7.15(2H, d, J=8.3 Hz), 7.35(1H, t,J=7.5 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.66(6H, m), 7.70(1H, t, J=7.4Hz), 7.91(1H, dd, J=8.7 and 1.4 Hz), 7.96-8.01(3H, m), 8.42(1H, s),12.65(1H, s).

IR(KBr): 1685 cm⁻¹.

mp: 164.5-167.0° C.

EXAMPLE 111 Synthesis of5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole(176)

In the same manner as in Example 98, 0.286 g of5-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-trifluoromethylbenzimidazole(176) were formed from 0.270 g of1-(biphenyl-4-ylmethyl)-5-carboxy-2-trifluoromethylbenzimidazole, 0.221g of N,N'-carbonyldiimidazole, 0.214 g of benzenesulfonamide and 0.207 gof diazabicycloundecene.

Properties of Compound (176):

¹ H-NMR(DMSO-d6, δ): 5.79(2H, s), 7.15(2H, d, J=8.1 Hz), 7.35(1H, t,J=7.5 Hz), 7.43(2H, t, J=7.5 Hz), 7.59-7.67(6H, m), 7.72(1H, t, J=7.6Hz), 7.83(1H, d, J=8.8 Hz), 7.94(1H, d, J=8.9 Hz), 8.02(2H, d, J=7.4Hz), 8.49(1H, s), 12.69(1H, s).

IR(KBr): 1699 cm⁻¹.

mp: 248.5-251.0° C.

EXAMPLE 112 Synthesis of6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole(177)

In the same manner as in Example 98, 0.730 g of6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole(177) were formed from 0.930 g of6-carboxy-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole, 0.972 g ofN,N'-carbonyldiimidazole, 0.942 g of benzenesulfonamide and 0.906 g ofdiazabicycloundecene.

Properties of Compound (177):

¹ H-NMR (DMSO-d6, δ): 1.04 (4H, m), 2.15 (1H, m), 5.70 (2H, s), 6.85(1H, t, J=7.5 Hz), 7.12 (1H, t, J=7.5 Hz), 7.22-7.38 (2H, m), 7.54-7.70(5H, m), 7.99 (2H, d, J=7.5 Hz), 8.11 (1H, s).

white powder.

EXAMPLE 113 Synthesis ofN-benzenesulfonyl-3-1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acrylamide(178)

In the same manner as in Example 98, 1.05 g ofN-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acrylamide(178) were formed from 1.10 g of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylic acid, 1.09 g ofN,N'-carbonyldiimidazole, 1.06 g of benzenesulfonamide and 1.02 g ofdiazabicycloundecene.

Properties of Compound (178):

¹ H-NMR(DMSO-d6, δ): 2.47(3H ,s), 5.55(2H, s), 6.46-6.55(2H, m),7.22(1H, t, J=7.6 Hz), 7.32(1H, t, J=7.7 Hz), 7.40(1H, d, J=8.4 Hz),7.52-7.66(6H, m), 7.69(1H, t), 7.93(2H, d, J=7.9 Hz), 12.17(1H, br s).

IR(KBr): 1687 cm⁻¹.

Mass(FAB): m/e 466(M+1).

mp: 243.1-244.3° C.

EXAMPLE 114 Synthesis ofN-benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acetamide(179)

In the same manner as in Example 98, 0.09 g ofN-benzenesulfonyl-2-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]acetamide(179) were formed from 0.170 g of1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetic acid, 0.175 g ofN,N'-carbonyldiimidazole, 0.170 g of benzenesulfonamide and 0.164 g ofdiazabicycloundecene.

Properties of Compound (179):

¹ H-NMR(DMSO-d6, δ): 2.44(3H, s), 3.57(2H, s), 5.46(2H, s), 6.41(1H, d,J=7.7 Hz), 6.96(1H, d, J=7.0 Hz), 7.16(1H, s), 7.20(1H, t), 7.32(1H, t),7.47(1H, d, J=8.2 Hz), 7.52-7.59(3H, m), 7.67(1H, t, J=7.5 Hz), 7.84(2H,d, J=7.4 Hz), 12.28(1H, br s).

IR(KBr) 1719 cm⁻¹.

mp: 236.2-237.8° C.

EXAMPLE 115 Synthesis of1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(180)

Dichloromethane (150 ml) and some drops of N,N-dimethylformamide wereadded to 9.00 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, and the mixturewas cooled with ice. Oxalyl chloride (6.84 g) were added dropwisethereto, and the mixed solution was stirred for some minutes. Further,this solution was stirred at room temperature for 1.5 hours, and wasthen concentrated to a volume of approximately 1/3 of the originalvolume under reduced pressure. The solid material precipitated wascollected, and was added to a solution of 2.69 g of2-aminomethylpyridine and 7.34 g of triethylamine in 200 ml ofdichloromethane in some divided portions. After the mixture was stirredfor 15 hours, the reaction solution was washed three times with waterand then with a saturated aqueous solution of sodium hydrogencarbonate.The organic layer was concentrated under reduced pressure, and wascrystallized from ethyl acetate. The crystals were separated throughfiltration, and were dried to give 4.35 g of1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(180).

Properties of Compound (180):

¹ H-NMR(CDCl₃, δ): 2.56(3H, s), 4.76(2H, d, J=4.8 Hz), 5.40(2H, s),6.33(1H, d, J=8.4 Hz), 7.07(1H, dd, J=8.4 and 2.0 Hz), 7.22(1H, dd,J=7.4 and 4.9 Hz), 7.33(1H, d, J=7.9 Hz), 7.48(1H, d, J=2.1 Hz),7.62-7.79(4H, m), 7.86(1H, d, J=1.1 Hz)8.57, (1H, d, J=4.9 Hz).

IR(KBr): 1645 cm⁻¹.

mp: 204.5-206.5° C.

EXAMPLE 116 Synthesis of1-methyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (181)

In the same manner as in Example 115, 0.213 g of1-methyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (181)were formed from 0.402 g of 6-carboxy-1-methyl-2-n-propylbenzimidazole,0.468 g of oxalyl chloride, 0.199 g of 2-aminomethylpyridine and 0.559 gof triethylamine.

Properties of Compound (181):

¹ H-NMR(CDCl₃, δ): 1.08(3H, t, J=7.4 Hz) 1.92(2H, m) 2.88(2H, m)3.76(3H, s) 4.80(2H, d, J=4.8 Hz), 7.22(1H, dd, J=2.5 and 7.5 Hz),7.35(1H, d, J=7.8 Hz), 7.67-7.77(4H, m), 7.80(1H, s), 8.58(1H, dd, J=4.9and 0.9 Hz).

IR(KBr): 1647 cm⁻¹.

mp: 140.5-141.5° C.

EXAMPLE 117 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(182)

In the same manner as in Example 115, 0.164 g of1-(2-chlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(182) were formed from 0.300 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.253 g of oxalylchloride, 0.108 g of 2-aminomethylpyridine and 0.302 g of triethylamine.

Properties of Compound (182):

¹ H-NMR(CDCl₃, δ): 2.56(3H, s), 4.76(2H, d, J=4.8 Hz), 5.45(2H, s),6.40(1H, d, J=7.8 Hz), 7.08(1H, t, J=7.6 Hz), 7.20-7.27(2H, m), 7.33(1H,d, J=7.8 Hz), 7.45(1H, dd, J=0.9 and 8.1 Hz), 7.64(1H, s), 7.65-7.69(1H,m), 7.72(1H, dd, J=1.5 and 8.4 Hz), 7.77(1H, d, J=8.4 Hz), 7.88(1H, d,J=1.2 Hz), 8.56(1H, d, J=4.7 Hz).

IR(KBr): 1646 cm⁻¹.

mp: 156.5-157.5° C.

EXAMPLE 118 Synthesis of2-n-propyl-1-i-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (183)

In the same manner as in Example 115, 0.020 g of2-n-propyl-1-i-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (183)were formed from 0.095 g of6-carboxy-2-n-propyl-1-i-propylbenzimidazole, 0.100 g of oxalylchloride, 0.039 g of 2-aminomethylpyridine and 0.097 g of triethylamine.

Properties of Compound (183):

¹ H-NMR(CDCl₃, δ): 1.08(3H, t, J=7.4 Hz), 1.69(6H, d, J=7.1 Hz),1.87-1.93(2H, m), 2.90(2H, t, J=7.8 Hz), 4.69-4.75(1H, m), 4.80(2H, d,J=4.9 Hz), 7.23(1H, dd, J=7.3 and 2.1 Hz), 7.37(1H, d, J=7.7 Hz),7.62-7.77(4H, m), 8.21(1H, s), 8.58(1H, d, J=4.5 Hz).

IR(KBr): 1631 cm⁻¹.

mp: 155.0-156.9° C.

EXAMPLE 119 Synthesis of1-n-butyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (184)

In the same manner as in Example 115, 0.283 g of1-n-butyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (184)were formed from 0.500 g of 1-n-butyl-6-carboxy-2-n-propylbenzimidazole,0.487 g of oxalyl chloride, 0.208 g of 2-aminomethylpyridine and 0.582 gof triethylamine.

Properties of Compound (184):

¹ H-NMR(CDCl₃, δ): 0.97(3H, t, J=7.3 Hz), 1.08(3H, t, J=7.4 Hz),1.37-1.46(2H, m), 1.76-1.83(2H, m), 1.92-2.00(2H, m), 2.86(2H, t, J=7.8Hz), 4.15(2H, t, J=7.6 Hz), 4.81(2H, d, J=4.8 Hz), 7.23(1H, dd, J=7.3and 2.4 Hz), 7.36(1H, d, J=7.8 Hz), 7.63-7.76(4H, m), 8.02(1H, s),8.58(1H, d, J=4.7 Hz).

IR(KBr): 1631 cm⁻¹.

mp: 105.8-107.2° C.

EXAMPLE 120 Synthesis of1-(3-chlorobenzyl)-2-n-propyl-6-[2-pyridylmethyl)carbamoyl]benzimidazole(185)

In the same manner as in Example 115, 0.311 g of1-(3-chlorobenzyl)-2-n-propyl-6-[2-pyridylmethyl)carbamoyl]benzimidazole(185) were formed from 0.580 g of6-carboxy-1-(3-chlorobenzyl)-2-n-propylbenzimidazole, 0.407 g of oxalylchloride, 0.173 g of 2-aminomethylpyridine and 0.486 g of triethylamine.

Properties of Compound (185):

¹ H-NMR(CDCl₃, δ): 1.03(3H, t, J=7.4 Hz), 1.85-1.93(2H, m), 2.80(2H, t,J=7.5 Hz), 4.77(2H, d, J=4.8 Hz), 5.36(2H, s), 6.86(1H, d, J=7.4 Hz),7.02(1H, s), 7.20-7.28(3H, m), 7.33(1H, d, J=7.8 Hz), 7.63-7.73(3H, m),7.79(1H, d, J=8.4 Hz), 7.91(1H, d, J=1.3 Hz), 8.57(1H, d, J=4.7 Hz).

IR(KBr): 1643 cm⁻¹.

mp: 157.7-158.8° C.

EXAMPLE 121 Synthesis of1-benzyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (186)

In the same manner as in Example 115, 0.350 g of1-benzyl-2-n-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (186)were formed from 0.850 g of 1-benzyl-6-carboxy-2-n-propylbenzimidazole,0.949 g of oxalyl chloride, 0.404 g of 2-aminomethylpyridine and 1.132 gof triethylamine.

Properties of Compound (186):

¹ H-NMR(CDCl₃, δ): 1.01(3H, t, J=7.4 Hz), 1.83-1.92(2H, m), 2.82(2H, t,J=7.6 Hz), 4.77(2H, d, J=4.8 Hz), 5.40(2H, s), 7.03(2H, d, J=6.5 Hz),7.21(1H, dd, J=7.1 and 2.1 Hz), 7.18-7.34(4H, m), 7.60(1H, s),7.65-7.72(2H, m), 7.78(1H, d, J=8.4 Hz), 7.94(1H, d, J=1.2 Hz),8.56(1H,d,J=4.2 Hz).

IR(KBr): 1642 cm⁻¹.

mp: 121.9-123.1° C.

EXAMPLE 122 Synthesis of1-(4-chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(187)

In the same manner as in Example 115, 0.089 g of1-(4-chlorobenzyl)-2-propyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(187) were formed from 0.547 g of6-carboxy-1-(4-chlorobenzyl)-2-propylbenzimidazole, 0.384 g of oxalylchloride, 0.163 g of 2-aminomethylpyridine and 0.458 g of triethylamine.

Properties of Compound (187):

¹ H-NMR(CDCl₃, δ): 1.02(3H, t, J=7.4 Hz), 1.84-1.92(2H, m),2.77-2.83(2H, m), 4.76(2H, d, J=4.8 Hz), 5.36(2H, s), 6.96(2H, d, J=8.3Hz), 7.22(1H, dd, J=6.4 and 0.4 Hz), 7.27(2H, dd, J=8.3 and 1.3 Hz),7.33(1H, d, J=7.8 Hz), 7.62-7.73(3H, m), 7.78(1H, d, J=8.4 Hz), 7.91(1H,d, J=0.9 Hz), 8.56(1H, dd, J=4.9 and 0.8 Hz).

IR(KBr): 1643 cm⁻¹.

mp: 158.8-161.0° C.

EXAMPLE 123 Synthesis of2-benzyl-1-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (188)

In the same manner as in Example 115, 0.171 g of2-benzyl-1-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (188) wereformed from 0.310 g of 2-benzyl-6-carboxy-1-methylbenzimidazole, 0.295 gof oxalyl chloride, 0.108 g of 2-aminomethylpyridine and 0.303 g oftriethylamine.

Properties of Compound (188):

¹ H-NMR(CDCl₃, δ): 3.66(3H, s), 4.35(2H, s), 4,80(2H, d, J=4.8 Hz),7.21-7.37(7H, m), 7.66(1H, br t), 7.67-7.73(2H, m), 7.78(1H, d, J=8.4Hz), 7.98(1H, s), 8.58(1H, d, J=4.9 Hz).

IR(KBr): 1632 cm⁻¹.

mp: 168.5-169.5° C.

EXAMPLE 124 Synthesis of1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(189)

In the same manner as in Example 115, 0.040 g of1-(2,6-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(189) were formed from 0.600 g of6-carboxy-1-(2,6-dichlorobenzyl)-2-methylbenzimidazole, 0.472 g ofoxalyl chloride, 0.201 g of 2-aminomethylpyridine and 0.188 g oftriethylamine.

Properties of Compound (189):

¹ H-NMR(CDCl₃, δ): 2.62(3H, s), 4.76(2H, d, J=4.7 Hz), 5.62(2H, s),7.23(1H, dd, J=7.1 and 2.2 Hz), 7.28(1H, d, J=7.8 Hz), 7.32(1H, d, J=7.9Hz), 7.39(2H, d, J=8.1 Hz), 7.54(1H, s), 7.66-7.71(3H, m), 7.78(1H, s),8.60(1H, d, J=4.6 Hz).

IR(KBr): 1635 cm⁻¹.

mp: 225.7-226.9° C.

EXAMPLE 125 Synthesis of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[2-(trifluoromethyl)benzyl]benzimidazole(190)

In the same manner as in Example 115, 0.713 g of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[2-(trifluoromethyl)benzyl]benzimidazole(190) were formed from 0.970 g of6-carboxy-2-methyl-1-[2-(trifluoromethyl)benzyl]benzimidazole, 0.736 gof oxalyl chloride, 0.261 g of 2-aminomethylpyridine and 0.726 g oftriethylamine.

Properties of Compound (190):

¹ H-NMR(CDCl₃, δ): 2.54(3H, s), 4.76(2H, d, J=4.8 Hz), 5.59(2H, s),6.45(1H, d, J=7.9 Hz), 7.22(1H, t, J=5.8 Hz), 7.34(2H, t, J=8.8 Hz),7.40(1H, t, J=7.5 Hz), 7.62(1H, br s), 7.68(1H, dt, J=1.7 and 7.7 Hz),7.72-7.82(3H, m), 7.87(1H, s), 8.56(1H, d, J=4.9 Hz).

IR(KBr): 1648 cm⁻¹.

mp: 172-174° C.

EXAMPLE 126 Synthesis of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]benzimidazole(191)

In the same manner as in Example 115, 0.194 g of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(trifluoromethyl)benzyl]benzimidazole(191) were formed from 0.970 g of6-carboxy-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole, 0.736 gof oxalyl chloride, 0.261 g of 2-aminomethylpyridine and 0.726 g oftriethylamine.

Properties of Compound (191):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.77(2H, d, J=4.7 Hz), 5.45(2H, s),7.15(2H, d, J=8.2 Hz), 7.23(1H, m), 7.33(1H, d, J=7.9 Hz), 7.58(2H, d,J=8.2 Hz), 7.63(1H, br s), 7.67-7.74(2H, m), 7.77(1H, d, J=8.3 Hz),7.93(1H, s), 8.57(1H, d, J=4.9 Hz).

IR(KBr): 1637 cm⁻¹.

mp: 188.5-190.0° C.

EXAMPLE 127 Synthesis of1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(192)

In the same manner as in Example 115, 0.264 g of1-(3,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(192) were formed from 0.500 g of6-carboxy-1-(3,4-dichlorobenzyl)-2-methylbenzimidazole, 0.393 g ofoxalyl chloride, 0.167 g of 2-aminomethylpyridine and 0.469 g oftriethylamine.

Properties of Compound (192):

¹ H-NMR(CDCl₃, δ): 2.58(3H, s), 4.77(2H, d, J=4.8 Hz), 5.33(2H, s),6.85(1H, dd, J=8.3 and 2.2 Hz), 7.14(1H, d, J=2.1 Hz), 7.22(1H, dd,J=7.3 and 5.6 Hz), 7.33(1H, d, J=7.8 Hz), 7.38(1H, d, J=8.3 Hz),7.65-7.77(4H, m), 7.92(1H, d, J=1.2 Hz), 8.57(1H, d, J=4.8 Hz).

IR(KBr): 1638 cm⁻¹.

mp: 219.0-220.7° C.

EXAMPLE 128 Synthesis of2-methyl-1-(2-methylbenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(193)

In the same manner as in Example 115, 0.100 g of2-methyl-1-(2-methylbenzyl)-6-[(² -pyridylmethyl)carbamoyl]benzimidazole(193) were formed from 0.453 g of6-carboxy-2-methyl-1-(2-methylbenzyl)benzimidazole, 0.411 g of oxalylchloride, 0.175 g of 2-aminomethylpyridine and 0.490 g of triethylamine.

Properties of Compound (193):

¹ H-NMR(CDCl₃, δ): 2.42(3H, s), 2.54(3H, s), 4.75(2H, d, J=4.9 Hz),5.32(2H, s), 6.33(1H, d, J=7.8 Hz), 7.01(1H, t, J=7.8 Hz), 7.17-7.24(3H,m), 7.33(1H, d, J=7.8 Hz), 7.60(1H, s), 7.63-7.73(2H, m), 7.76(1H, d,J=8.4 Hz), 7.84(1H, d, J=1.4 Hz), 8.56(1H, d, J=4.9 Hz).

IR(KBr): 1635 cm⁻¹.

mp: 154.0-157.0° C.

EXAMPLE 129 Synthesis of1-(2-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(194)

In the same manner as in Example 115, 0.918 g of1-(2-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(194) were formed from 0.997 g of6-carboxy-1-(2-methoxybenzyl)-2-methylbenzimidazole, 0.858 g of oxalylchloride, 0.309 g of 2-aminomethylpyridine and 1.02 g of triethylamine.

Properties of Compound (194):

¹ H-NMR(CDCl₃, δ): 2.60(3H, s), 3.89(3H, s), 4.77(2H, d, J=4.8 Hz),5.36(2H, s), 6.60(1H, d, J=7.4 Hz), 6.79(1H, dt, J=0.8 and 7.4 Hz),6.91(1H, d, J=7.4 Hz), 7.20-7.28(2H, m), 7.34(1H, d, J=7.9 Hz), 7.56(1H,br t), 7.66-7.75(3H, m), 7.95(1H, m), 8.57(1H, d, J=4.9 Hz).

IR(KBr): 1652 cm⁻¹.

mp: 136-138.5° C.

EXAMPLE 130 Synthesis of1-(4-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(195)

In the same manner as in Example 115, 0.697 g of1-(4-methoxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(195) were formed from 0.985 g of6-carboxy-1-(4-methoxybenzyl)-2-methylbenzimidazole, 0.858 g of oxalylchloride, 0.309 g of 2-aminomethylpyridine and 1.02 g of triethylamine.

Properties of Compound (195):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 3.76(3H, s), 4.78(2H, d, J=4.8 Hz),5.32(2H, s), 6.83(2H, m), 7.00(2H, m), 7.22(1H, dd, J=5.1 and 6.8 Hz),7.34(1H, d, J=7.8 Hz), 7.60(1H, br t), 7.67-7.76(3H, m), 7.97(1H, d,J=1.2 Hz), 8.57(1H, d, J=4.9 Hz).

IR(KBr): 1652 cm⁻¹.

mp: 191.5-192.2° C.

EXAMPLE 131 Synthesis of1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(196)

In the same manner as in Example 115, 0.64 g of1-[2-(benzenesulfonylmethyl)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(196) were formed from 0.74 g of1-[2-(benzenesulfonylmethyl)benzyl]-6-carboxy-2-methylbenzimidazole,0.45 g of oxalyl chloride, 0.19 g of 2-aminomethylpyridine and 0.53 g oftriethylamine.

Properties of Compound (196):

¹ H-NMR(CDCl₃, δ): 2.57(3H, s), 4.50(2H, s), 4.74(2H, d, J=4.9 Hz),5.59(2H, s), 6.63(1H, d, J=7.7 Hz), 6.87(1H, d, J=7.4 and 1.5 Hz),7.09-7.19(3H, m), 7.31(1H, d, J=7.8 Hz), 7.53-7.61(3H, m), 7.64(1H, dt,J=7.6 and 1.6 Hz), 7.68-7.79(5H, m), 7.84(1H, s), 8.52(1H, d, J=4.8 Hz).

IR(neat) 1646 cm⁻¹.

liquid.

EXAMPLE 132 Synthesis of1-(2-cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(197)

In the same manner as in Example 115, 1.03 g of1-(2-cyanobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(197) were formed from 1.14 g of6-carboxy-1-(2-cyanobenzyl)-2-methylbenzimidazole, 0.998 g of oxalylchloride, 0.425 g of 2-aminomethylpyridine and 1.19 g of triethylamine.

Properties of Compound (197):

¹ H-NMR(CDCl₃, δ): 2.58(3H, s), 4.76(2H, d, J=4.8 Hz), 5.59(2H, s),6.64(1H, d, J=7.4 Hz), 7.21(1H, dt, J=5.6 and 1.8 Hz), 7.33(1H, d, J=7.9Hz), 7.39-7.47(2H, m), 7.65-7.79(5H, m), 7.89(1H, s), 8.56(1H, dd, J=4.9and 0.9 Hz).

IR(KBr): 2223, 1642 cm⁻¹.

mp: 150.5-151.4° C.

EXAMPLE 133 Synthesis of1-(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(198)

In the same manner as in Example 115, 0.672 g of1-(biphenyl-2-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(198) were formed from 1.07 g of1-(biphenyl-2-ylmethyl)-6-carboxy-2-methylbenzimidazole, 0.796 g ofoxalyl chloride, 0.339 g of 2-aminomethylpyridine and 0.950 g oftriethylamine.

Properties of Compound (198):

¹ H-NMR(CDCl₃, δ): 2.38(3H, s), 4.78(2H, d, J=4.8 Hz), 5.27(2H, s),6.64(1H, d, J=8.0 Hz), 7.17-7.24(2H, m), 7.29-7.43(6H, m), 7.48(2H, t,J=5.5 Hz), 7.49(1H, s), 7.57-7.73(3H, m), 7.80(1H, d, J=1.0 Hz),8.58(1H, d, J=4.9 Hz).

IR(KBr): 1630, 1619 cm⁻¹.

mp: 179.8-180.8° C.

EXAMPLE 134 Synthesis of1-benzyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (199)

In the same manner as in Example 115, 0.66 g of1-benzyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (199) wereformed from 0.59 g of 1-benzyl-6-carboxy-2-methylbenzimidazole, 0.56 gof oxalyl chloride, 0.24 g of 2-aminomethylpyridine and 0.67 g oftriethylamine.

Properties of Compound (199):

¹ H-NMR(CDCl₃, δ): 2.58(3H, s), 4.76(2H, d, J=4.9 Hz), 5.36(2H, s),7.02-7.06(2H, m), 7.21(1H, dd, J=6.9 and 5.0 Hz), 7.27-7.35(4H, m),7.65-7.75(4H, m), 7.96(1H, d, J=0.8 Hz), 8.56(1H, d, J=4.8 Hz).

IR(KBr): 1640 cm⁻¹.

mp: 124.0-124.9° C.

EXAMPLE 135 Synthesis of1-(4-tert-butylbenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(200)

In the same manner as in Example 115, 0.477 g of1-(4-tert-butylbenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(200) were formed from 0.544 g of1-(4-tert-butylbenzyl)-6-carboxy-2-methylbenzimidazole, 0.428 g ofoxalyl chloride, 0.183 g of 2-aminomethylpyridine and 0.511 g oftriethylamine.

Properties of Compound (200):

¹ H-NMR(CDCl₃, δ): 1.27(9H, s), 2.60(3H, s), 4.77(2H, d, J=4.9 Hz),5.34(2H, s), 6.98(2H, d, J=8.3 Hz), 7.21(1H, dd, J=7.3 and 5.1 Hz),7.29-7.35(3H, m), 7.62(1H, br s), 7.65-7.75(3H, m), 7.96(1H, d, J=1.1Hz), 8.57(1H, d, J=4.7 Hz).

IR(KBr): 1646 cm⁻¹.

mp: 140.4-142.8° C.

EXAMPLE 136 Synthesis of2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(201)

In the same manner as in Example 115, 0.47 g of2-methyl-1-(2-naphthylmethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(201) were formed from 0.80 g of6-carboxy-2-methyl-1-(2-naphthylmethyl)benzimidazole, 0.64 g of oxalylchloride, 0.27 g of 2-aminomethylpyridine and 0.77 g of triethylamine.

Properties of Compound (201):

¹ H-NMR(CDCl₃, δ): 2.60(3H, s), 4.75(2H, d, J=4.9 Hz), 5.52(2H, s),7.17-7.23(2H, m), 7.31(1H, d, J=7.8 Hz), 7.38(1H, s), 7.43-7.48(2H, m),7.60-7.82(7H, m), 8.00(1H, d, J=1.0 Hz), 8.53(1H, d, J=4.7 Hz).

IR(KBr): 1640 cm⁻¹.

mp: 143.0-144.5° C.

EXAMPLE 137 Synthesis of1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(202)

In the same manner as in Example 115, 0.410 g of1-(biphenyl-4-ylmethyl)-2-ethyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(202) were formed from 0.500 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.356 g ofoxalyl chloride, 0.151 g of 2-aminomethylpyridine and 0.424 g oftriethylamine.

Properties of Compound (202):

¹ H-NMR(CDCl₃, δ): 1.45(3H, t, J=7.7 Hz), 2.90(2H, q, J=7.4 Hz),4.77(2H, d, J=4.7 Hz), 5.43(2H, s), 7.10(2H, d, J=8.2 Hz), 7.20(1H, dt,J=4.9 and 7.7 Hz), 7.33(2H, t, J=7.4 Hz), 7.42(2H, t, J=7.5 Hz),7.49-7.55(4H, m), 7.61(1H, br t), 7.67(1H, dt, J=7.8 and 1.8 Hz),7.72(1H, d, J=8.4 Hz), 7.81(1H, d, J=8.4 Hz), 7.99(1H, s), 8.56(1H, d,J=4.9 Hz).

IR(KBr): 1640 cm⁻¹.

mp: 123.0-124.0° C.

EXAMPLE 138 Synthesis of1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]benzimidazole (203)

In the same manner as in Example 115, 0.110 g of1-(2-chlorobenzyl)-6-[2-(pyridylmethyl)carbamoyl]benzimidazole (203)were formed from 0.461 g of 6-carboxy-1-(2-chlorobenzyl)benzimidazole,0.728 g of oxalyl chloride, 0.174 g of 2-aminomethylpyridine and 0.486 gof triethylamine.

Properties of Compound (203):

¹ H-NMR(CDCl₃, δ): 4.78(2H, d, J=4.8 Hz), 5.51(2H, s), 6.92(1H, d, J=6.5Hz), 7.17-7.31(3H, m), 7.34(1H, d, J=7.8 Hz), 7.45(1H, dd, J=1.1 and 8.0Hz), 7.69(1H, dt, J=1.8 and 7.7 Hz), 7.67-7.73(1H, br s), 7.76(1H, dd,J=1.5 and 8.4 Hz), 7.87(1H, d, J=8.4 Hz), 8.05(2H, s), 8.57(1H, d, J=4.9Hz).

IR(KBr): 1646 cm⁻¹.

mp: 144.0-145.0° C.

EXAMPLE 139 Synthesis of2-methyl-1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(204)

In the same manner as in Example 115, 0.241 g of2-methyl-1-(2-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(204) were formed from 0.367 g of6-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole, 0.299 g of oxalylchloride, 0.217 g of 2-aminomethylpyridine and 0.360 g of triethylamine.

Properties of Compound (204):

¹ H-NMR(CDCl₃, δ): 2.56(3H, s), 4.75(2H, d, J=4.8 Hz), 5.83(2H, s),6.41(1H, d, J=7.8 and 1.2 Hz), 7.22(1H, dt, J=5.0 and 1.7 Hz), 7.32(1H,d, J=7.9 Hz), 7.43-7.52(2H, m), 7.64(1H, s), 7.68(1H, dt, J=7.6 and 1.7Hz),7.75(1H, dd, J=8.4 and 1.5 Hz), 7.80(1H, d, J=8.4 Hz), 7.82(1H, d,J=1.3 Hz), 8.28(1H, dd, J=8.0 and 1.7 Hz), 8.56(1H, d, J=4.9 Hz).

IR(KBr): 1645 cm⁻¹.

mp: 194.8-196.7° C.

EXAMPLE 140 Synthesis of2-methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(205)

In the same manner as in Example 115, 0.079 g of2-methyl-1-(2-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(205) were formed from 0.096 g of5-carboxy-2-methyl-1-(2-nitrobenzyl)benzimidazole, 0.078 g of oxalylchloride, 0.048 g of 2-aminomethylpyridine and 0.093 g of triethylamine.

Properties of Compound (205):

¹ H-NMR(CDCl₃, δ): 2.57(3H, s), 4.80(2H, d, J=4.7 Hz), 5.80(2H, s),6.43(1H, d, J=7.4 and 0.8 Hz), 7.17(1H, d, J=8.4 Hz), 7.22(1H, dt, J=5.5and 1.8 Hz), 7.35(1H, d, J=7.8 Hz), 7.44-7.52(2H, m), 7.67(1H, s),7.69(1H, dt, J=7.8 and 1.9 Hz), 7.82(1H, dd, J=8.4 and 1.5 Hz), 8.27(1H,dd, J=8.0 and 1.6 Hz), 8.28(1H, d, J=1.4 Hz), 8.56(1H, d, J=4.9 Hz).

IR(KBr): 1645 cm⁻¹.

mp: ˜96° C.(decomp.).

EXAMPLE 141 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalenesulfonylcarbamoyl)benzimidazolesodium salt (206)

N,N'-carbonyldiimidazole (0.541 g) was added at a time to a solution of0.500 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, a solution of 0.689 g of2-naphthalenesulfonamide and 0.506 g of diazabicycloundecene in 5 ml ofN,N-dimethylformamide were added thereto, and the mixture was stirred at100° C. for 48 hours. The reaction solution was cooled, and the solventwas distilled off under reduced pressure. Water and chloroform wereadded to the residue, and 10% hydrochloric acid was added thereto untilthe aqueous layer was acidified. The mixture was extracted twice withchloroform. A saturated aqueous solution of sodium hydrogencarbonate wasadded to the resulting organic layer, and the mixed solution wasstirred. The crystals precipitated were separated through filtration,and were dissolved in a small amount of methanol. Further, ethyl acetatewas added thereto for crystallization. The crystals were separatedthrough filtration, and were dried to give 0.508 g of1-(2-chlorobenzyl)-2-methyl-6-(2-naphthalenesulfonylcarbamoyl)benzimidazolesodium salt (206).

Properties of Compound (206):

¹ H-NMR(DMSO-d6, δ): 2.46(3H, s), 5.51(2H, s), 6.38(1H, d, J=7.9 Hz),7.17(1H, t, J=7.5 Hz), 7.30(1H, t), 7.45(1H, d, J=8.5 Hz), 7.51-7.57(3H,m), 7.77-7.93(5H, m), 7.99(1H, m), 8.35(1H, s).

IR(KBr): 1594 cm⁻¹.

Mass(FAB): m/e 512(M+1).

mp: 352.0-354.5° C.

EXAMPLE 142 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalenesulfonylcarbamoyl)benzimidazolesodium salt (207)

In the same manner as in Example 141, 0.390 g of1-(2-chlorobenzyl)-2-methyl-6-(1-naphthalenesulfonylcarbamoyl)benzimidazolesodium salt (207) were formed from 0.600 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.647 g ofN,N'-carbonyldiimidazole, 0.829 g of 1-naphthalenesulfonamide and 0.608g of diazabicycloundecene.

Properties of Compound (207):

¹ H-NMR(DMSO-d6, δ): 2.46(3H, s), 5.49(2H, s), 6.39(1H, d, J=7.8 Hz),7.16(1H, t, J=7.5 Hz), 7.31(1H, t, J=7.3 Hz), 7.36(1H, t), 7.40-7.45(2H,m), 7.50(1H, t, J=7.7 Hz), 7.54(1H, d, J=8.0 Hz), 7.75-7.81(2H, m),7.87(1H, d, J=7.9 Hz), 7.93(1H, d, J=8.2 Hz), 8.09(1H, d, J=7.3 Hz),8.86(1H, d, J=8.5 Hz).

IR(KBr): 1633 cm⁻¹.

Mass(FAB): m/e 512(M+1).

mp: ˜265° C.(decomp.).

EXAMPLE 143 Synthesis of6-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazolesodium salt (208)

In the same manner as in Example 141, 0.270 g of6-(4-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazolesodium salt (208) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.432 g ofN,N'-carbonyldiimidazole, 0.510 g of 4-chlorobenzenesulfonamide and0.404 g of diazabicycloundecene.

Properties of Compound (208):

¹ H-NMR(DMSO-d6, δ): 2.46(3H, s), 5.52(2H, s), 6.38(1H, d, J=7.4 Hz),7.19(1H, t, J=7.6 Hz), 7.31(1H, t, J=7.6 Hz), 7.39(2H, d, J=8.5 Hz),7.45(1H, d, J=8.9 Hz), 7.54(1H, d, J=8.0 Hz), 7.76-7.82(4H, m).

IR(KBr): 1592 cm⁻¹.

Mass(FAB): m/e 496(M+1).

mp: 360-362° C.(decomp.).

EXAMPLE 144 Synthesis of6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(209)

In the same manner as in Example 141,6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazolesodium salt was obtained from 0.450 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g ofN,N'-carbonyldiimidazole, 0.573 g of 3-chlorobenzenesulfonamide and0.456 g of diazabicycloundecene. This salt was dissolved in a mixedsolution of methanol and water, and was adjusted to a pH of from 5 to 6with 10% hydrochloric acid. The crystals precipitated were separatedthrough filtration, and were dried to give 0.420 g of6-(3-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(209).

Properties of Compound (209):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 5.63(2H, s), 6.48(1H, d, J=7.7 Hz),7.22(1H, t, J=7.6 Hz), 7.34(1H, t, J=7.7 Hz), 7.56(1H, t, J=8.0 Hz),7.64(1H, t, J=8.0 Hz), 7.68(1H, d, J=8.5 Hz), 7.78(2H, t, J=8.6 Hz),7.91(1H, d, J=7.6 Hz), 7.95(1H, d, J=1.6 Hz), 8.10(1H, s).

IR(KBr): 1687 cm⁻¹.

Mass(FAB): m/e 474(M+1).

mp: 254.5-257.5° C.(decomp.).

EXAMPLE 145 Synthesis of5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole(210)

In the same manner as in Example 144, 0.447 g of5-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole(210) were formed from 0.466 g of2-benzyl-5-carboxy-1-(2-chlorobenzyl)benzimidazole, 0.401 g ofN,N'-carbonyldiimidazole, 0.389 g of benzenesulfonamide and 0.377 g ofdiazabicycloundecene.

Properties of Compound (210):

¹ H-NMR(DMSO-d6, δ): 4.28(2H, s), 5.57(2H, s), 6.23(1H, d, J=7.6 Hz),7.04(1H, t, J=7.6 Hz), 7.10-7.26(6H, m), 7.40(1H, d, J=8.6 Hz), 7.46(1H,d, J=8.0 Hz), 7.61-7.73(4H, m), 8.00(2H, d, J=7.6 Hz), 8.23(1H, s),12.43(1H, br s).

IR(KBr): 1685 cm⁻¹.

mp: 152.0-155.0° C.

EXAMPLE 146 Synthesis of6-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole(211)

In the same manner as in Example 144, 0.803 g of6-benzenesulfonylcarbamoyl-2-benzyl-1-(2-chlorobenzyl)benzimidazole(211) were formed from 0.760 g of2-benzyl-6-carboxy-1-(2-chlorobenzyl)benzimidazole, 0.654 g ofN,N'-carbonyldiimidazole, 0.634 g of benzenesulfonamide and 0.614 g ofdiazabicycloundecene.

Properties of Compound (211):

¹ H-NMR(DMSO-d6, δ): 4.41(2H, s), 5.71(2H, s), 6.32(1H, d, J=7.7 Hz),7.06(1H, t, J=7.7 Hz), 7.14-7.30(6H, m), 7.50(1H, d, J=8.0 Hz), 7.62(2H,t), 7.70(1H, t), 7.81(1H, d, J=8.6 Hz), 7.87(1H, d, J=8.5 Hz), 7.97(2H,d, J=8.2 Hz), 8.16(1H, s), 12.60(1H, br s).

IR(KBr): 1704 cm⁻¹.

mp: 143.0-144.5° C.

EXAMPLE 147 Synthesis of1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(180)

Ten milliliters of dichloromethane and 1 drop of N,N-dimethylformamidewere added to 0.627 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, and the mixturewas cooled with ice. Oxalyl chloride (0.493 g) was added dropwisethereto, and the mixture was stirred for several minutes. Further, themixture was stirred at room temperature for 1 hour, and was thenconcentrated under reduced pressure to remove oxalyl chloride. Theresidue was dissolved in 10 ml of dichloromethane. This solution wasadded dropwise to a solution of 0.167 g of 2-aminomethylpyridine and0.469 g of triethylamine in 5 ml of methylene chloride while beingcooled with ice. After the mixture was stirred for 1 hour, the reactionsolution was washed three times with water and further with a saturatedaqueous solution of sodium hydrogencarbonate. The organic layer wasconcentrated under reduced pressure, and was purified throughpreparative thin-layer silica-gel chromatography (eluent: a mixture ofacetone and diethyl ether at a ratio of 1:1). The resulting product wasfurther dissolved in 5 ml of ethyl acetate, and 2 ml of hexane wereadded thereto for crystallization. The crystals were separated throughfiltration, and were dried to give 0.359 g of1-(2,4-dichlorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(180).

Properties of Compound (180):

¹ H-NMR(CDCl₃, δ): 2.56(3H, s), 4.76(2H, d, J=4.8 Hz), 5.40(2H, s),6.33(1H, d, J=8.4 Hz), 7.07(1H, dd, J=8.4 and 2.0 Hz), 7.22(1H, dd,J=7.4 and 4.9 Hz), 7.33(1H, d, J=7.9 Hz), 7.48(1H, d, J=2.1 Hz),7.62-7.79(4H, m), 7.86(1H, d, J=1.1 Hz), 8.57, (1H, d, J=4.9 Hz).

IR(KBr): 1645 cm⁻¹.

mp: 204.1-206.3° C.

EXAMPLE 148 Synthesis of1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(212)

Oxalyl chloride (0.655 g) was added to a solution of 0.886 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methylbenzimidazole and 1 drop ofN,N-dimethylformamide in 13 ml of dichloromethane while being cooledwith ice, and the mixture was stirred at room temperature for 15 hours.The crystals precipitated were separated through filtration, washed withmethylene chloride, and dried under reduced pressure. The crystals wereadded to a solution of 0.235 g of 2-aminomethylpyridine and 0.653 g oftriethylamine in 15 ml of dichloromethane while being cooled, and themixture was stirred for 1 hour. Water was added to the reaction solutionto stop the reaction. The reaction solution was washed twice with waterand further with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was then dried, and the solvent wasconcentrated under reduced pressure. The residue was recrystallized froma mixed solvent of ethyl acetate and ethanol to give 0.774 g of1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(212).

Properties of Compound (212):

¹ H-NMR(CDCl₃, δ): 2.62(3H, s), 4.77(2H, d, J=4.8 Hz), 5.42(2H, s),7.12(2H, d, J=8.5 Hz), 7.21(1H, m), 7.34(2H, m), 7.42(2H, m),7.51-7.55(4H, m),7.62(1H, br t), 7.67(1H, dt, J=1.7 and 7.7 Hz),7.71(1H, dd, J=1.6 and 8.4 Hz), 7.76(1H, d, J=8.4 Hz), 8.00(1H, d, J=1.2Hz), 8.56(1H, d, J=4.8 Hz).

IR(KBr): 1642 cm⁻¹.

mp: 205.0-206.5° C.

EXAMPLE 149 Synthesis of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163)

N,N'-carbonyldiimidazole (0.973 g) was added to a solution of 0.902 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 ml ofN,N-dimethylformamide, and the mixture was stirred at room temperaturefor 1 hour. Subsequently, a solution of 0.943 g of benzenesulfonamideand 0.913 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide wasadded thereto, and the mixture was stirred at 100° C. for 70 hours. Thereaction solution was cooled, and the solvent was distilled off underreduced pressure. Water and chloroform were added to the residue, and10% hydrochloric acid was added thereto while being stirred until theaqueous layer was acidified. The mixed solution was extracted twice withchloroform. The resulting organic layer was washed with a saturatedaqueous solution of sodium hydrogencarbonate, and the solvent wasdistilled off under reduced pressure. The residue was dissolved in asmall amount of chloroform, and ethyl acetate was added to the solutionfor crystallization. The crystals were separated through filtration, andwere dried to give 0.667 g of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163).

EXAMPLE 150 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazolesodium salt (213)

In the same manner as in Example 141, 0.365 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazolesodium salt (213) were formed from 0.637 g of6-carboxy-1-(biphenyl-4-ylmethyl)-2-methylbenzimidazole, 0.533 g ofN,N'-carbonyldiimidazole, 0.516 g of benzenesulfonamide and 0.500 g ofdiazabicycloundecene.

Properties of Compound (213):

¹ H-NMR(DMSO-d6, δ): 2.52(3H, s), 5.52(2H, S), 7.13(2H, d, J=8.1 Hz),7.31-7.37(4H, m), 7.39-7.45(3H, m), 7.58-7.63(4H, m), 7.78-7.82(3H, m),7.97(1H, s).

IR(Nujol): 1591 cm⁻¹.

mp: 289.0-290.0° C.(decomp.).

EXAMPLE 151 Synthesis of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163)

N,N'-carbonyldiimidazole (5.41 g) was added at a time to a solution of5.02 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 110 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, a solution of 5.24 g ofbenzenesulfonamide and 5.08 g of diazabicycloundecene in 20 ml ofN,N-dimethylformamide was added thereto, and the mixed solution wasstirred at 100° C. for 70 hours. The reaction solution was cooled, andthe solvent was distilled off under reduced pressure. Water andchloroform were added to the residue, and 10% hydrochloric acid wasadded thereto while being stirred until the aqueous layer was acidified.The solution was extracted twice with chloroform. The organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate,and a part of the solvent was distilled off under reduced pressure. Thecrystals precipitated were separated through filtration, and were driedto give 4.96 g of6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163).

EXAMPLE 152 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazolehydrochloride (214)

N,N'-carbonyldiimidazole (0.647 g) was added at a time to a solution of0.600 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, a solution of 0.596 g oftrifluoromethanesulfonamide and 0.609 g of diazabicycloundecene in 5 mlof N,N-dimethylformamide was added thereto, and the mixture was stirredat 100° C. for 72 hours. The reaction solution was cooled, and thesolvent was distilled off under reduced pressure. Water and ethylacetate were added to the residue, and 10% hydrochloric acid was addedthereto while being stirred until the aqueous layer was acidified. Thecrystals precipitated were washed with a mixed solvent of 25 ml ofethanol and 25 ml of methanol. The crystals were dried to give 0.420 gof1-(2-chlorobenzyl)-2-methyl-6-trifluoromethanesulfonylcarbamoylbenzimidazolehydrochloride (214).

Properties of Compound (214):

¹ H-NMR(DMSO-d6, δ): 2.84(3H, s), 5.82(2H, s), 7.08(1H, d, J=7.5 Hz),7.30(1H, t), 7.40(1H, t, J=7.7 Hz), 7.58(1H, d, J=8.0 Hz), 7.79(1H, d,J=8.6 Hz), 8.07-8.13(2H, m).

IR(KBr): 1634 cm⁻¹.

Mass(CI): m/e 432(M+1-HCl).

mp: 332-335° C.(decomp.).

EXAMPLE 153 AND 154 Synthesis of6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazolehydrochloride (215) and6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(216)

In the same manner as in Example 152, 0.540 g of6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazolehydrochloride (215) were formed from 0.460 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.455 g ofN,N'-carbonyldiimidazole, 0.431 g of benzenesulfonamide and 0.418 g ofdiazabicycloundecene.

Properties of Compound (215):

¹ H-NMR(DMSO-d6, δ): 2.71(3H, s), 5.74(2H, s), 6.83(1H, d, J=8.4 Hz),7.33(1H, dd, J=2.0 and 8.4 Hz), 7.63(2H, t), 7.71(1H, t), 7.78(1H, d,J=2.0 Hz), 7.86(1H, d, J=8.7 Hz), 7.95(1H, dd, J=1.4 and 8.7 Hz),7.99(2H, m), 8.29(1H, s).

IR(KBr): 1686 cm⁻¹.

mp: 236.0-238.0° C.

This compound was dissolved in a mixed solvent of a potassiumhydrogencarbonate and methanol, and the solution was adjusted to a pH offrom 5 to 6 with 10% hydrochloric acid. The crystals precipitated werecollected, washed with water and with methanol, and dried to give6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(216).

Properties of Compound (216):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 5.58(2H, s), 6.42(1H, d, J=8.4 Hz),7.31(1H, dd, J=2.2 and 8.4 Hz), 7.60-7.75(6H, m), 7.99(2H, d, J=7.4 Hz),8.06(1H, s), 12.40(1H, s).

IR(KBr): 1540 cm⁻¹.

mp: 238.2.-239.9° C.

EXAMPLE 155 Synthesis of1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole(217)

N,N'-carbodiimidazole (0.431 g) was added at a time to a solution of0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, a solution of 0.498 g of4-methoxybenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 mlof N,N-dimethylformamide was added thereto, and the mixed solution wasstirred at 100° C. for 67 hours. The reaction solution was cooled, andthe solvent was distilled off under reduced pressure. Water andchloroform were added to the residue, and 10% hydrochloric acid wasadded thereto while being cooled until the aqueous layer was acidified.The resulting mixture was extracted twice with chloroform. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate, and the solvent was distilled off under reducedpressure. The residue was purified through silica-gel columnchromatography (eluent: a mixture of chloroform and methanol at a ratioof 100:2 to 100:10). The resulting product was concentrated, and wascrystallized from a mixed solution of ethyl acetate and diethyl ether.The crystals were separated through filtration, and were dried to give0.450 g of1-(2-chlorobenzyl)-6-(4-methoxybenzenesulfonylcarbamoyl)-2-methylbenzimidazole(217).

Properties of Compound (217):

¹ H-NMR(DMSO-d6, δ): 2.46(3H, s), 3.83(3H, s), 5.58(2H, s), 7.12(2H, d,J=9.0 Hz), 7.21(1H, t, J=7.3 Hz), 7.33(1H, t), 7.56(1H, d, J=7.0 Hz),7.63(1H, d, J=8.5 Hz), 7.71(1H, dd, J=1.6 and 8.5 Hz), 7.91(2H, d, J=9.0Hz), 8.05(1H, d, J=1.3 Hz).

IR(KBr): 1683 cm⁻¹.

Mass(FAB): m/e 470(M+1).

mp: 271.0-274.0° C.

EXAMPLE 156 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(α-toluenesulfonylcarbamoyl)benzimidazole(218)

In the same manner as in Example 155, 0.350 g of1-(2-chlorobenzyl)-2-methyl-6-(α-toluenesulfonylcarbamoyl)benzimidazole(218) were formed from 0.450 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g ofN,N-carbonyldiimidazole, 0.512 g of a-toluenesulfonamide and 0.456 g ofdiazabicycloundecene.

Properties of Compound (218):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 4.36(2H, s), 5.53(2H, s), 6.40(1H, d,J=6.8 Hz), 7.15-7.28(6H, m), 7.32(1H, t), 7.49(1H, d, J=8.3 Hz),7.55(1H, d), 7.83-7.87(2H, m).

IR(KBr): 1593 cm⁻¹.

Mass(FAB): m/e 454(M+1).

mp: 193-196° C.(foamed)

EXAMPLE 157 Synthesis of1-(2-chlorobenzyl)-6-(2,5-dimethylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole(219)

In the same manner as in Example 155, 0.490 g of1-(2-chlorobenzyl)-6-(2,5-dimethylbenzenesulfonylcarbamoyl)-2-methylbenzimidazole(219) were formed from 0.500 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.539 g ofN,N'-carbonyldiimidazole, 0.616 g of 2,5-xylenesulfonamide and 0.506 gof diazabicycloundecene.

Properties of Compound (219):

¹ H-NMR(DMSO-d6, δ): 2.35(3H, s), 2.48(3H, s), 2.51(3H, s), 5.58(2H, s),6.45(1H, d, J=7.5 Hz), 7.20-7.27(2H, m), 7.31-7.39(2H, m), 7.56(1H, d,J=8.0 Hz), 7.64(1H, d, J=8.5 Hz), 7.75(1H, d, J=8.5 Hz), 7.82(1H, s),8.06(1H, s), 12.45(1H, br s).

IR(KBr): 1690 cm⁻¹.

Mass(FAB): m/e 468(M+1).

mp: 266.5-267.5° C.

EXAMPLE 158 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole(220)

N,N'-carbodiimidazole (0.432 g) was added at a time to a solution of0.400 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 mlof N,N-dimethylformamide, and the solution was stirred at roomtemperature for 1 hour. Subsequently, a solution of 0.538 g of4-nitrobenzenesulfonamide and 0.405 g of diazabicycloundecene in 5 ml ofN,N-dimethylformamide, and the mixture was stirred at 100° C. for 84hours. The reaction solution was cooled, and the solvent was distilledoff under reduced pressure. Chloroform and hydrochloric acid were addedto the residue, and the mixture was stirred to precipitate the crystals.The crystals precipitated were separated through filtration, and weredried to give 0.300 g of1-(2-chlorobenzyl)-2-methyl-6-(4-nitrobenzenesulfonylcarbamoyl)benzimidazole(220).

Properties of Compound (220):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.65(2H, s), 6.54(1H, d, J=7.6 Hz),7.23(1H, t, J=7.6 Hz), 7.34(1H, t, J=7.6 Hz), 7.56(1H, t, J=8.0 Hz),7.68(1H, d, J=8.5 Hz), 7.83(1H, d, J=8.3 Hz), 8.07(1H, s),8.16(2H,d,J=8.7 Hz), 8.37(2H, d, J=8.7 Hz).

IR(KBr): 1621 cm⁻¹.

Mass(FAB): m/e 485(M+1).

mp: 330-332° C.

EXAMPLE 159 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)benzenesulfonylcarbamoyl]benzimidazole(221)

In the same manner as in Example 158, 0.390 g of1-(2-chlorobenzyl)-2-methyl-6-[4-(trifluoromethyl)benzenesulfonylcarbamoyl]benzimidazole(221) were formed from 0.450 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g ofN,N'-carbonyldiimidazole, 0.676 g of4-(trifluoromethyl)benzenesulfonamide and 0.457 g ofdiazabicycloundecene.

Properties of Compound (221):

¹ H-NMR(DMSO-d6, δ): 2.52(3H, s), 5.62(2H, s), 6.47(1H, d, J=7.2 Hz),7.22(1H, t, J=7.5 Hz), 7.34(1H, t), 7.56(1H, d, H=8.0 Hz), 7.66(1H, d,8.5 Hz), 7.78(1H, d), 7.97(2H, d, J=8.3 Hz), 8.06(1H, s), 8.15(2H, d,J=8.3 Hz).

IR(KBr): 1620 cm⁻¹.

Mass(FAB): m/e 508(M+1).

mp: 288.0-292.0° C.

EXAMPLE 160 Synthesis of6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazoleammonium salt (222)

N,N'-carbodiimidazole (0.485 g) was added at a time to a solution of0.450 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 15 mlof N,N-dimethylformamide and the mixture was stirred at room temperaturefor 1 hour. Subsequently, a solution of 0.575 g oftrifluoromethanesulfonamide and 0.457 g of diazabicycloundecene in 5 mlof N,N-dimethylformamide was added thereto, and the mixture was stirredat 100° C. for 72 hours. The reaction solution was cooled, and thesolvent was distilled off under reduced pressure. Water and ethylacetate were added to the residue, and 10% hydrochloric acid was addedthereto while being mixed until the aqueous layer was acidified. Thecrystals precipitated were separated through filtration. The crystalswere dissolved in ethanol, and the solution was adjusted to a pH of 7with aqueous ammonia. Further, diisopropyl ether was added thereto. Thecrystals precipitated were separated through filtration, and were driedto give 0.360 g of6-(2-chlorobenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazoleammonium salt (222).

Properties of Compound (222):

¹ H-NMR(DMSO-d6, δ): 2.47(3H, s), 5.51(2H, s), 6.43(1H, d, J=7.5 Hz),7.12(4H, br s), 7.19(1H, t, J=7.6 Hz), 7.28-7.38(4H, m), 7.46(1H, d,J=8.3 Hz), 7.53(1H, d, J=7.9 Hz), 7.78-7.82(2H, m), 7.97(1H, m).

IR(KBr): 1590 cm⁻¹.

Mass(FAB): m/e 474(M+1-NH3).

mp: 264.0-267.0° C.

EXAMPLE 161 Synthesis of6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (223)

Oxalyl chloride (0.437 g) was added to a solution of 0.490 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and 1 drop ofN,N-dimethylformamide in 8 ml of methylene chloride while being cooledwith ice, and the mixture was stirred at room temperature for 1.5 hours.Four milliliters of 28% aqueous ammonia were added thereto, and thesolution was stirred at room temperature for 12 hours. The reactionsolution was extracted with the addition of water and methylenechloride. The organic layer was concentrated, and the crystalsprecipitated were then collected, and were dried to give 0.240 g of6-carbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (223).

Properties of Compound (223):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 5.54(2H, s), 6.41(1H, d, J=8.4 Hz),7.21-8.02(3H, m), 7.31(1H, dd, J=2.2 and 8.4 Hz), 7.60(1H, d, J=8.4 Hz),7.75(1H, m), 7.93(1H, s).

IR(KBr): 1666 cm⁻¹.

mp: 112.0-114.0° C.

EXAMPLE 162 Synthesis of6-benzensulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole(224)

N,N'-carbonyldiimidazole (0.248 g) was added at a time to a solution of0.315 g of 2-benzyl-6-carboxy-1-(2,4-dichlorobenzyl)benzimidazole in 5ml of N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1 hour. Subsequently, a solution of 0.240 g ofbenzenesulfonamide and 0.233 g of diazabicycloundecene in 4 ml ofN,N-dimethylformamide was added thereto, and the mixture was stirred at100° C. for 62 hours. The reaction solution was cooled, and the solventwas distilled off under reduced pressure. Water and chloroform wereadded to the residue, and 10% hydrochloric acid was added thereto whilebeing mixed until the aqueous layer was acidified. The solution wasextracted twice with chloroform. The resulting organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate, and apart of the solvent was distilled off under reduced pressure. To theresidue were added 4 ml of methanol and 4 ml of a 20% potassiumhydrogencarbonate aqueous solution to form a uniform solution. Thissolution was then adjusted to a pH of from 5 to 6 with 10% hydrochloricacid. The crystals precipitated were separated through filtration, andwere dried to give 0.310 g of6-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole(244).

Properties of Compound (224):

¹ H-NMR(DMSO-d6, δ): 4.32(1H, s), 5.61(2H, s), 6.16(1H, d, J=8.4 Hz),7.09(1H, dd, J=8.4 and 1.9 Hz), 7.18-7.10(5H, m), 7.82-7.58(6H, m),7.97(2H, d, J=7.6 Hz), 8.10(1H, s), 12.43(1H, br s).

IR(KBr): 1703 cm⁻¹.

mp: 236.0-238.0° C.

EXAMPLE 163 Synthesis of5-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole(225)

In the same manner as in Example 152, 0.270 g of5-benzenesulfonylcarbamoyl-2-benzyl-1-(2,4-dichlorobenzyl)benzimidazole(225) were formed from 0.385 g of2-benzyl-5-carboxy-1-(2,4-dichlorobenzyl)benzimidazole, 0.304 g ofN,N'-carbonyldiimidazole, 0.294 g of benzenesulfonamide and 0.285 g ofdiazabicycloundecene.

Properties of Compound (225):

¹ H-NMR(DMSO-d6, δ): 4.28(2H, s), 5.52(2H, s), 6.14(1H, d, J=8.4 Hz),7.21-7.06(6H, m), 7.42(1H, d, J=8.6 Hz), 7.76-7.57(5H, m), 8.05-7.95(2H,m), 8.24(1H, s), 12.43(1H, br s).

IR(KBr): 1691 cm⁻¹.

mp: 107.0-110.0° C.

EXAMPLE 164 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-2-hydroxybenzimidazole(226)

Tetramethoxymethane (0.220 g) was added to a solution of 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 mlof acetic acid, and the mixture was stirred at 80° C. for 2 hours. Thereaction solution was concentrated, and a 20% potassiumhydrogencarbonate aqueous solution was added to this reaction solutionto render it basic. This solution was then adjusted to a pH of from 5 to6 with 10% hydrochloric acid. The crystals precipitated were collected,and 10 ml of methanol, 0.50 g of 10% hydrochloric acid and 0.35%hydrochloric acid were added thereto. The mixture was stirred at 60° C.for 15 hours. A 20% potassium hydrogencarbonate aqueous solution wasadded to the solution to render it alkaline. This solution was thenadjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystalsprecipitated were separated through filtration, and were dried to give0.219 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-2-hydroxybenzimidazole(226).

Properties of Compound (226):

¹ H-NMR(DMSO-d6, δ): 5.07(2H, s), 7.08(1H, d, J=8.2 Hz), 7.33-7.39(3H,m), 7.44(2H, t, J=7.5 Hz), 7.60-7.65(7H, m), 7.66-7.72(2H, m),7.96-7.80(2H, m), 11.46(1H, s), 12.34(1H, s).

IR(KBr): 1704, 1686 cm⁻¹.

Mass(FD): m/e 483(M).

mp: 268.7-273.9° C.

EXAMPLE 165 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole(227)

Two milliliters of carbon disulfide were added to a solution of 0.800 gofN-benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,and the mixture was stirred at 50° C. for 70 hours. Chloroform and waterwere added thereto. The crystals precipitated were separated throughfiltration, and were dried to give 0.719 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazole(227).

Properties of Compound (227):

¹ H-NMR(DMSO-d6, δ): 5.55(2H, s), 7.28(1H, d, J=8.4 Hz), 7.35(1H, t,J=6.3 Hz), 7.39-7.47(4H, m), 7.61-7.65(6H, m), 7.69(1H, t, J=7.4 Hz),7.78(1H, dd, J=8.4 and 1.4 Hz), 7.87(1H, s), 7.81-7.98(2H, m), 12.51(1H,s), 13.29(1H, s).

IR(KBr): 1701 cm⁻¹.

mp: 320.0-321.0° C.

EXAMPLE 166 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole(228)

Tetramethoxymethane (0.250 g) was added to a solution of 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 3 mlof acetic acid, and the mixture was stirred at 80° C. for 2 hours.Methanol was added to the reaction solution, and the crystalsprecipitated were collected. The crystals were washed with a mixedsolvent of 1 ml of acetone and 8 ml of methanol, separated throughfiltration, and dried to give 0.280 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxybenzimidazole(228).

Properties of Compound (228):

¹ H-NMR(DMSO-d6, δ): 4.17(3H, s), 5.33(2H, s), 7.30(2H, d, J=8.2 Hz),7.35(1H, t, J=7.4 Hz), 7.44(2H, t, J=7.5 Hz), 7.50(1H, d, J=8.4 Hz),7.60-7.65(6H, m), 7.68-7.72(2H, m), 7.98-8.01(2H, m), 8.05(1H, d, J=1.5Hz), 8.18(1H, s), 12.50(1H, s).

IR(KBr): 1690 cm⁻¹.

mp: 136.0-138.5° C.

EXAMPLE 167 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole(229)

Triethylamine (0.080 g) and 0.148 g of methyloxalyl chloride were addedto a solution of 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 3 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was concentrated, and theresidue was purified through silica-gel column chromatography (eluent: amixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crude6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole.This compound was dissolved in 1 ml of acetic acid and 5 ml of methanol,and the mixture was stirred at 60° C. for 15 hours. The reactionsolution was neutralized with a potassium hydroxide aqueous solution.The crystals precipitated were separated through filtration, and weredried to give 0.245 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-carboxybenzimidazole(229).

Properties of Compound (229):

¹ H-NMR(DMSO-d6, δ): 5.44(2H, s), 7.23(1H, d, J=8.4 Hz), 7.36(1H, t,J=7.6 Hz), 7.41(2H, d, J=8.1 Hz), 7.45(2H, t, J=7.5 Hz), 7.58(2H, t,J=7.8 Hz), 7.60-7.71(7H, m), 7.94(2H, d, J=8.3 Hz), 12.38(1H, s),12.52(1H, s).

IR(KBr): 1670 cm⁻¹.

mp: 247.5-250.0° C.

EXAMPLE 168 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylaminobenzimidazole(230)

A mixture containing 0.300 g ofN-benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,0.200 g of methyl isothiocyanate, 5 ml of methanol and 5 ml of acetonewas stirred at room temperature for 12 hours. Further, 1 ml of 97%sulfuric acid was added thereto, and the mixture was stirred at roomtemperature for 43 hours. A 20% potassium hydrogencarbonate aqueoussolution was added to the reaction solution to render it basic. Thisreaction solution was then concentrated, and the residue was extractedwith ethyl acetate and with water. The organic layer was concentrated,dissolved in chloroform, and precipitated with hexane. The crystalsprecipitated were separated through filtration, and were dried to give0.140 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylaminobenzimidazole(230).

Properties of Compound (230):

¹ H-NMR(DMSO-d6, δ): 2.98(3H, d, J=4.4 Hz), 5.34(2H, s), 7.22(2H, d,J=8.2 Hz), 7.26(1H, d, J=8.4 Hz), 7.34(1H, t, J=7.3 Hz), 7.44(2H, t,J=7.5 Hz), 7.57(2H, t, J=7.6 Hz), 7.59-7.68(6H, m), 7.76(1H, s),7.95(2H, d, J=7.4 Hz), 12.28(1H, s).

IR(KBr): 1672 cm⁻¹.

Mass(FAB): m/e 497(M+1).

mp: 225.0-228.0° C.

EXAMPLE 169 Synthesis of2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole(231)

Ten milliliters of methanol, 10 ml of acetone and 0.395 g of cyanogenbromide were added to 1.500 g ofN-benzenesulfonylcarbamoyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide,and the mixture was stirred at room temperature for 100 hours and thenat 50° C. for 30 hours. The reaction solution was extracted withchloroform and with water. The organic layer was washed six times withwater, and was concentrated. The residue was purified through silica-gelcolumn chromatography (eluent: a mixture of ethyl acetate and methanolat a ratio of 9:1) to give 0.135 g of2-amino-6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole(231).

Properties of Compound (231):

¹ H-NMR(DMSO-d6, δ): 5.32(2H, s), 6.77(2H, s), 7.05(1H, d, J=8.8 Hz),7.21(2H, d, J=8.3 Hz), 7.31-7.38(4H, m), 7.43(2H, t, J=7.5 Hz),7.58-7.65(6H, m), 7.79-7.82(2H, m).

IR(KBr): 1684 cm⁻¹.

Mass(FAB): m/e 483(M+1).

mp: 352.5-355.0° C.

EXAMPLE 170 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazolepotassium salt (232)

Triethylamine (0.060 g) and 0.084 g of butyryl chloride were added to asolution of 0.300 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 2 mlof N,N-dimethylformamide, and the mixture was stirred at roomtemperature for 1.5 hours. The reaction solution was directly purifiedthrough silica-gel column chromatography to obtain 0.250 g ofN-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-butyrylaminobenzamide.To this compound were added 5 ml of methanol and 0.50 g of 35%hydrochloric acid, and the mixture was stirred at 60° C. for 3 hours.Then, 20% potassium hydrogencarbonate was added thereto to stop thereaction, and the reaction solution was extracted with ethyl acetate andwith water. The organic layer was concentrated, and the product wasdissolved in a small amount of chloroform. Ether was added thereto forcrystallization. The crystals precipitated were separated throughfiltration, and were dried to give 0.157 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazolepotassium salt (232).

Properties of Compound (232):

¹ H-NMR(DMSO-d6, δ): 0.95(3H, t, J=7.4 Hz), 1.77(2H, q, J=7.5 Hz),2.82(2H, t, J=7.5 Hz), 5.55(2H, s), 7.11(2H, d, J=8.2 Hz), 7.32-7.38(4H,m), 7.43(2H, t, J=7.5 Hz), 7.47(1H, d, J=8.4 Hz), 7.58-7.64(4H, m),7.79-7.83(3H, m), 7.96(1H, s).

IR(Nujol): 1592 cm⁻¹.

Mass(FAB): m/e 548(M+1).

mp: 279.0-282.0° C.

EXAMPLE 171 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-heptylbenzimidazole(233)

In the same manner as in Example 170, 0.232 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-heptylbenzimidazole(233) were formed from 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide, 0.080 gof triethylamine and 0.170 g of octanoyl chloride.

Properties of Compound (233):

¹ H-NMR(DMSO-d6, δ): 0.79(3H, t, J=7.3 Hz), 1.12-1.24(6H, m),1.24-1.31(2H, m), 1.66-1.73(2H, m), 2.84(2H, t, J=7.6 Hz), 5.58(2H, s),7.14(2H, d, J=8.1 Hz), 7.34(2H, t, J=7.6 Hz), 7.43(2H, t, J=7.4 Hz),7.52-7.66(7H, m), 7.75(1H, d, J=8.8 Hz), 7.95(2H, d, J=7.6 Hz), 8.15(1H,s), 12.45(1H, s). IR(KBr): 1688 cm⁻¹.

mp: 112.0-117.5° C.

EXAMPLE 172 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethylbenzimidazole(234)

In the same manner as in Example 170, 0.913 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-chloromethylbenzimidazole(234) were formed from 0.300 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide, 0.060 gof triethylamine and 0.102 of chloroacetyl chloride.

Properties of Compound (234):

¹ H-NMR(DMSO-d6, δ): 5.10(2H, s), 5.71(2H, s), 7.23(2H, d, J=8.3 Hz),7.35(1H, t, J=7.3 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.66(6H, m), 7.69(1H,t, J=7.5 Hz), 7.75-7.81(2H, m), 7.98-8.01(2H, m), 8.16(1H, s), 12.52(1H,s).

IR(KBr): 1700 cm⁻¹.

mp: 220.5-223.5° C.

EXAMPLE 173 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxymethylbenzimidazole(235)

In the same manner as in Example 170, 0.183 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methoxymethylbenzimidazole(235) were formed from 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide, 0.115 gof triethylamine and 0.131 g of methoxyacetyl chloride.

Properties of Compound (235):

¹ H-NMR(DMSO-d6, δ): 3.31(3H, s), 4.72(2H, s), 5.63(2H, s), 7.23(2H, d,J=8.3 Hz), 7.35(1H, t, J=7.4 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.65(6H,m), 7.70(1H, t, J=7.5 Hz), 7.72-7.79(2H, m), 7.98-8.01(2H, m), 8.18(1H,s), 12.50(1H, s).

IR(KBr): 1690 cm⁻¹.

mp: 195.0-198.0° C.

EXAMPLE 174 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-i-propylbenzimidazolepotassium salt (236)

In the same manner as in Example 170, 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide, 0.080 gof triethylamine and 0.112 g of isobutyryl chloride were reacted asstarting materials. The crude product was dissolved in a mixed solventof methanol and a 20% potassium hydrogencarbonate aqueous solution, andthe pH was adjusted to 7 with 10% hydrochloric acid. The crystalsprecipitated were crystals of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-i-propylbenzimidazolepotassium salt [(236), 0.167 g].

Properties of Compound (236):

¹ H-NMR(DMSO-d6, δ): 1.26(6H, d, J=6.8 Hz), 3.25-3.40(1H, m), 5.58(2H,s), 7.09(2H, d, J=8.3 Hz), 7.32-7.37(4H, m), 7.43(2H, t, J=7.5 Hz),7.48(1H, d, J=8.4 Hz), 7.58-7.64(4H, m), 7.79-7.83(3H, m), 7.95(1H, s).

IR(Nujol): 1592 cm⁻¹.

Mass(FAB): m/e 548(M+1).

mp: 310.1-312.7° C.

EXAMPLE 175 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl-2-methylthiobenzimidazole(237)

A 20% potassium hydroxide aqueous solution (0.323 g), 2 ml of water and0.123 g of methyl iodide were added to a solution of 0.310 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazolein 5 ml of methanol in this order, and the mixture was stirred at roomtemperature for 2 hours. The reaction solution was adjusted to a pH offrom 5 to 6 with 10% hydrochloric acid. The crystals precipitated wereseparated through filtration, and were dried to give 0.281 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-methylthiobenzimidazole(237).

Properties of Compound (237):

¹ H-NMR(DMSO-d6, δ): 2.75(3H, s), 5.48(2H, s), 7.25(2H, d, J=8.3 Hz),7.35(1H, t, J=7.4 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.66(7H, m),7.68-7.75(2H, m), 7.82-7.99(2H, m), 8.19(1H, d, J=1.6 Hz), 12.43(1H, s).

IR(KBr): 1685 cm⁻¹.

mp: 218.8-220.4° C.

EXAMPLE 176 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylthiobenzimidazole(238)

In the same manner as in Example 175, 0.225 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-ethylthiobenzimidazole(238) were formed from 0.240 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazoleand 0.117 g of ethyl iodide.

Properties of Compound (238):

¹ H-NMR(DMSO-d6, δ): 1.39(3H, t, J=7.3 Hz), 3.37(2H, q, J=7.3 Hz),5.47(2H, s), 7.24(2H, d, J=8.1 Hz), 7.35(1H, t, J=7.1 Hz), 7.44(2H, t,J=7.6 Hz), 7.57-7.68(8H, m), 7.75(1H, d, J=8.4 Hz), 7.98(2H, d, J=7.5Hz), 8.15(1H, s), 12.43(1H, s).

IR(KBr): 1686 cm⁻¹.

mp: 125.5-129.5° C.

EXAMPLE 177 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylthiobenzimidazole(239)

In the same manner as in Example 175, 0.156 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylthiobenzimidazole(239) were formed from 0.220 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazoleand 0.117 g of n-propyl iodide.

Properties of Compound (239):

¹ H-NMR(DMSO-d6, δ): 0.97(3H, t, J=7.4 Hz), 1.76(2H, q, J=7.2 Hz),3.29-3.36(2H, m), 5.48(2H, s), 7.24(2H, d, J=8.3 Hz), 7.35(1H, t, J=7.3Hz), 7.44(2H, t, J=7.4 Hz), 7.58-7.71(8H, m), 7.74(1H, dd, J=8.5 and 1.7Hz), 7.99(2H, d, J=7.7 Hz), 8.17(1H, s), 12.43(1H, s).

IR(KBr): 1690 cm⁻¹.

mp: 106.0-111.5° C.

EXAMPLE 178 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthiobenzimidazole(240)

In the same manner as in Example 175, 0.212 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-hexylthiobenzimidazole(240) were formed from 0.250 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-mercaptobenzimidazoleand 0.166 g of n-hexyl iodide.

Properties of Compound (240):

¹ H-NMR(DMSO-d6, δ): 0.82(3H, t, J=7.9 Hz), 1.19-1.33(4H, m),1.33-1.44(2H, m), 1.68-1.75(2H, m), 3.30-3.43(2H, m), 5.48(2H, s),7.23(2H, d, J=8.2 Hz), 7.35(1H, t, J=7.1 Hz), 7.44(2H, t, J=7.6 Hz),7.60-7.75(9H, m), 8.00(2H, d, J=7.7 Hz), 8.19(1H, s), 12.44(1H, s).

IR(KBr): 1688 cm⁻¹.

mp: 139.5-141.0° C.(decomp.).

EXAMPLE 179 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole (241)

A mixture of 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide and 2 mlof formic acid was stirred at 90° C. for 3 hours. The reaction solutionwas concentrated, and was precipitated with methanol. The crystalsprecipitated were separated through filtration, and were dried to give0.243 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)benzimidazole (241).

Properties of Compound (241):

¹ H-NMR(DMSO-d6, δ): 5.60(2H, s), 7.35(1H, t, J=7.2 Hz), 7.39(2H, d,J=8.2 Hz), 7.44(2H, t, J=7.6 Hz), 7.61-7.77(9H, m), 8.00(2H, d, J=7.7Hz), 8.26(1H, s), 8.66(1H, s), 12.5(1H, s).

IR(KBr): 1683 cm⁻¹.

mp: 141.5-143.6° C.

EXAMPLE 180 Synthesis of1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(242)

Four milliliters of acetic acid and 8 ml of ethanol were added to 0.434g ofN-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide,and the mixture was stirred at 90° C. for 7 hours. The reaction solutionwas concentrated under reduced pressure. Ethyl acetate and ether wereadded to the residue for crystallization. The crystals were separatedthrough filtration, and were dried to give 0.375 g of1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(242).

Properties of Compound (242):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.78(2H, d, J=4.8 Hz), 5.01(2H, s),5.31(2H, s), 6.89(2H, d, J=8.7 Hz), 6.99(2H, d, J=8.6 Hz), 7.21(1H, dd,J=5.1 and 7.4 Hz), 7.29-7.42(6H, m), 7.62(1H, br t), 7.65-7.75(3H, m),7.98(1H, s), 8.57(1H, d, J=4.1 Hz).

IR(KBr): 1640 cm⁻¹.

mp: 169.0-170.0° C.

EXAMPLE 181 Synthesis of2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(243)

Two milliliters of acetic acid and 5 ml of methanol were added to 0.490g ofN-(2-pyridylmethyl)-4-acetylamino-3-(3,4-methylenedioxybenzylamino)benzamide,and the mixture was stirred at 70° C. for 8 hours. The reaction solutionwas concentrated under reduced pressure. The residue was purifiedthrough silica-gel column chromatography (eluent: a mixture of ethylacetate and methanol at a ratio of 9:1), and was then crystallized fromethyl acetate. The crystals were separated through filtration, and weredried to give 0.270 g of2-methyl-1-(3,4-methylenedioxybenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(243).

Properties of Compound (243):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.78(2H, d, J=4.8 Hz), 5.28(2H, s),5.93(2H, s), 6.51(1H, d, J=1.6 Hz), 6.55(1H, dd, J=1.4 and 7.9 Hz),6.72(2H, d, J=8.0 Hz), 7.22(1H, dd, J=6.7 and 5.0 Hz), 7.34(1H, d, J=7.7Hz), 7.62(1H, br t), 7.67-7.75(3H, m), 7.96(1H, d, J=1.1 Hz), 8.58(1H,d, J=4.9 Hz).

IR(KBr): 1637 cm⁻¹.

mp: 190.5-192.0° C.

EXAMPLE 182 Synthesis of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole(244)

In the same manner as in Example 180, 0.33 g of2-methyl-6-[(2-pyridylmethyl)carbamoyl]-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole(244) were formed from 0.50 g ofN-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide.

Properties of Compound (244):

¹ H-NMR(CDCl₃, δ): 2.58(3H, s), 4.58(2H, d, J=5.9 Hz), 5.62(2H, s),7.24(1H, dd, J=7.3 and 5.0 Hz), 7.28-7.33(3H, m), 7.64(1H, d, J=8.4 Hz),7.73(1H, dt, J=7.7 and 1.6 Hz), 7.81(1H, dd, J=8.4 and 1.3 Hz), 8.10(1H,d, J=8.2 Hz), 8.13(1H, s), 8.49(1H, d, J=4.2 Hz), 9.04(1H, t, J=5.9 Hz),9.58(1H, s).

IR(KBr): 1642 cm⁻¹.

mp: 216.0-217.0° C.

EXAMPLE 183 Synthesis of6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl-2-methylbenzimidazole(245)

N-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide(0.370 g) was dissolved in a mixed solvent of 3.3 g of 10% hydrochloricacid, 6 ml of methanol and 4 ml of water, and 0.5 g of 35% hydrochloricacid were further added thereto. The mixture was stirred at 60° C. for 3hours. A 20% potassium hydrogencarbonate aqueous solution was added tothe reaction solution to render it basic. Then, this solution wasadjusted to a pH of from 5 to 6 with 10% hydrochloric acid. The crystalsprecipitated were separated through filtration, and were dried to give0.182 g of6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl-2-methylbenzimidazole

Properties of Compound (245):

¹ H-NMR(DMSO-d6, δ): 2.53(3H, s), 5.56(2H, s), 6.95-7.01(1H, m),7.04(1H, dt, J=8.7 and 1.4 Hz), 7.32(1H, dt, J=10.7 and 2.1 Hz),7.59-7.66(3H, m), 7.68-7.74(2H, m), 8.00(2H, d, J=8.1 Hz), 8.13(1H, s),12.43(1H, s). IR(KBr): 1686 cm⁻¹.

mp: 234.5-235.5° C.(decomp.).

EXAMPLE 184 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole(246)

Triethylamine (0.115 g) and 0.200 g of benzoyl chloride were added to asolution of 0.500 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 5 mlof N,N-dimethylformamide. The mixture was stirred at room temperaturefor 15 hours. A potassium hydrogencarbonate aqueous solution was addedthereto to stop the reaction. The solvent was distilled off underreduced pressure. The residue was dissolved in a mixture of water andmethanol, and the solution was adjusted to a pH of from 5 to 6 with 10%hydrochloric acid. The crystals precipitated were collected, and weredried to obtain 0.393 g of crudeN-benzenesulfonyl-4-benzoylamino-3-(biphenyl-4-ylmethylamino)benzamide.This crude product was converted to6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-phenylbenzimidazole[(246), 0.270 g] in the same manner as in Example 183.

Properties of Compound (246):

¹ H-NMR(DMSO-d6, δ): 5.70(2H, s), 7.07(2H, d, J=8.2 Hz), 7.32-7.37(1H,m), 7.43(2H, t, J=5.7 Hz), 7.53-7.58(2H, m), 7.58-7.65(7H, m),7.68-7.72(1H, m), 7.77(2H, dd, J=7.5 and 1.5 Hz), 7.81-7.83(2H, m),7.98-8.02(2H, m), 8.22(1H, s), 12.47(1H, s).

IR(KBr): 1690 cm⁻¹.

mp: 138.5-139.5° C.

EXAMPLE 185 Synthesis of6-benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (247)

In the same manner as in Example 183, 0.237 g of6-benzenesulfonylcarbamoyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (247)were formed from 0.79 g ofN-benzenesulfonyl-4-acetylamino-3-(2-nitrobenzylamino)benzamide.

Properties of Compound (247):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 5.01(2H, s), 5.93(2H, s),6.28-6.30(1H, m), 7.55-7.62(4H, m), 7.64-7.74(3H, m), 7.97(2H, d, J=8.0Hz), 8.10(1H, s), 8.22-8.28(1H, m), 12.39(1H, s).

IR(KBr): 1686 cm⁻¹.

mp: 269.5-272.5(decomp.).

EXAMPLE 186 Synthesis of6-benzenesulfonylcarbamoyl-2-methyl-1-benzylbenzimidazole (248)

In the same manner as in Example 183, 0.222 g of6-benzenesulfonylcarbamoyl-2-methyl-1-benzylbenzimidazole (248) wereformed from 0.38 g ofN-benzenesulfonyl-4-acetylamino-3-benzylaminobenzamide.

Properties of Compound (248):

¹ H-NMR(DMSO-d6, δ): 2.54(3H, s), 5.55(2H, s), 7.12(2H, d, J=7.9 Hz),7.28(1H, t, J=7.3 Hz), 7.34(2H, t, J=7.0 Hz), 7.61-7.66(3H, m),7.69-7.76(2H, m), 8.00(2H, d, J=7.9 Hz), 8.18(1H, s), 12.43(1H, s).

IR(KBr): 1695 cm⁻¹.

mp: 260.0-262.0° C.(decomp.).

EXAMPLES 187 AND 188 Synthesis of6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazole (249)and 6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazolepotassium salt (250)

In the same manner as in Example 183, 0.255 g of6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazole (249)were formed as a crystal from 0.505 g ofN-benzenesulfonyl-4-acetylamino-3-(4-nitrobenzylamino)benzamide.Further, the filtrate was concentrated to form 0.136 g of6-benzenesulfonylcarbamoyl-2-methyl-1-(4-nitrobenzyl)benzimidazolepotassium salt (250) as a crystal.

Properties of Compound (249):

¹ H-NMR(DMSO-d6, δ): 2.50(3H, s), 5.70(2H, s), 7.30(2H, d, J=8.7 Hz),7.52(2H, t, J=7.6 Hz), 7.57(2H, d, J=8.3 Hz), 7.76(1H, dd, J=8.4 and 1.4Hz), 7.92(2H, d, J=7.3 Hz), 8.05(1H, s), 8.20(2H, d, J=8.7 Hz),12.43(1H, s).

IR(KBr): 1686 cm.

mp: 164.5-167.0° C.

Properties of Compound (250):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 5.68(2H, s), 7.28(2H, d, J=8.5 Hz),7.32-7.41(3H, m), 7.46(1H, d, J=8.4 Hz), 7.78-7.86(3H, m), 7.91(1H, s),8.20(2H, d, J=8.5 Hz).

IR(KBr): 1594 cm⁻¹.

mp: 326.0-328.0° C.(decomp.).

EXAMPLE 189 Synthesis of6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole(251)

A mixture containing 0.500 g ofN-benzenesulfonyl-3-amino-4-acetylaminobenzamide potassium salt, 0.470 gof 4-benzyloxybenzyl bromide, 0.925 g of a 20% potassiumhydrogencarbonate aqueous solution and 3 ml of N,N-dimethylformamide wasstirred at 90° C. for 1 hour. The reaction solution was concentrated,and was purified through silica-gel column chromatography (eluent: amixture of ethyl acetate and methanol at a ratio of 9:1) to obtain crudeN-benzenesulfonyl-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide.This crude product was cyclized in the same manner as in Example 183 togive 0.160 g of6-benzenesulfonylcarbamoyl-1-(4-benzyloxybenzyl)-2-methylbenzimidazole(251).

Properties of Compound (251):

¹ H-NMR(DMSO-d6, δ): 2.54(3H, s), 5.05(2H, s), 5.44(2H, s), 7.09(2H, d,J=8.7 Hz), 7.32(2H, d, J=7.0 Hz), 7.29-7.44(5H, m), 7.58-7.67(3H, m),7.68-7.75(2H, m), 7.79-8.02(2H, m), 8.18(1H, s), 12.46(1H, s).

IR(KBr): 1685 cm⁻¹.

mp: 111.0-114.0° C.

EXAMPLE 190 Synthesis of2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (252)

Five-percent palladium on carbon (0.10 g) was added to a mixture of 1.00g of crude N-(2-pyridylmethyl)-4-acetylamino-3-nitrobenzamide, 8 ml ofacetic acid and 12 ml of ethanol, and the solution was stirred in ahydrogen atmosphere at 80° C. for 7 hours. The solid material wasseparated through filtration, and the filtrate was concentrated. Ethylacetate was added to the residue for crystallization. The crystals wereseparated through filtration, and were dried to give 0.57 g of2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole (252).

Properties of Compound (252):

¹ H-NMR(CDCl₃, δ): 2.52(3H, s), 4.59(2H, d, J=5.9 Hz), 7.26(1H, dd,J=7.1 and 5.1 Hz), 7.33(1H, d, J=7.8 Hz), 7.50(1H, d, J=8.4 Hz),7.72-7.78(2H, m), 8.08(1H, s), 8.51(1H, d, J=4.8 Hz), 9.04(1H, t, J=5.8Hz), 12.44(1H, s).

IR(KBr): 1641 cm⁻¹.

mp: 212.0-215.0° C.

EXAMPLES 191 AND 192 Synthesis of1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(253) and1-benzenesulfonyl-2-methyl-5-[2-pyridylmethyl)carbamoyl]benzimidazole(254)

Ten milliliters of dichloromethane and 0.760 g of triethylamine wereadded to 1.00 g of 1-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,and 0.994 g of benzenesulfonyl chloride were added dropwise thereto. Themixture was stirred for 3 hours, and the reaction solution was washedthree times with water and then with a sodium hydrogencarbonate aqueoussolution. The organic layer was concentrated under reduced pressure, andwas purified through silica-gel column chromatography (eluent: a mixtureof ethyl acetate and methanol at a ratio of 9:1) to obtain 1.380 g of amixture of1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazoleand1-benzenesulfonyl-2-methyl-5-(2-pyridylmethyl)carbamoyl]benzimidazole.This mixture was further purified through medium-pressure silica-gelcolumn chromatography (eluent: a mixture of ethyl acetate and methanolat a ratio of 100:3) to give 0.550 g of oily1-benzenesulfonyl-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(253) and 0.540 g of oily1-benzenesulfonyl-2-methyl-5-[2-pyridylmethyl)carbamoyl]benzimidazole(254). These oily products were dissolved in 1.5 ml of methylenechloride, and were crystallized from diethyl ether.

Properties of Compound (253):

¹ H-NMR(CDCl₃, δ): 2.84(3H, s), 4.81(2H, d, J=4.8 Hz), 7.24(1H, dd,J=5.1 and 7.3 Hz), 7.37(1H, d, J=7.7 Hz), 7.53(2H, dd, J=7.9 and 7.5Hz), 7.63-7.74(2H, m), 7.85(1H, dd, J=8.4 and 1.2 Hz), 7.97(2H, dd,J=9.6 and 1.1 Hz), 8.58-8.61(2H, m).

IR(KBr): 1636 cm⁻¹.

mp: 163.4-164.3° C.

Properties of Compound (254):

¹ H-NMR(CDCl₃, δ):2.83(3H, s), 4.78(2H, d, J=4.7 Hz), 7.23(1H, dd, J=4.9and 8.6 Hz), 7.34(1H, d, J=7.9 Hz), 7.53(2H, dd, J=7.5 and 8.4 Hz),7.64-7.75(3H, m), 7.91-7.96(3H, m),8.10(1H, d, J=9.1 Hz), 8.14(1H, d,J=1.3 Hz), 8.56(1H, dd, J=4.9 and 1.0 Hz).

IR(KBr): 1657 cm⁻¹.

mp: 88.3-91.3° C.

EXAMPLES 193 AND 194 Synthesis of2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(255) and2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(256)

Ten milliliters of N,N-dimethylformamide, 3.24 g of 4-nitrobenzylbromide and 2.52 g of sodium hydrogencarbonate were added to 3.56 g of2-methyl-5-[2-pyridylmethyl)carbamoyl]benzimidazole, and the mixture washeated at 80° C. for 2 hours. The reaction solution was separated withthe addition of chloroform and water. The organic layer was concentratedunder reduced pressure, and was purified through silica-gel columnchromatography (eluent: a mixture of ethyl acetate and methanol at aratio of 4:1) to obtain a mixture of2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazoleand2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole.This mixture was further separated into position isomers throughmedium-pressure silica-gel column chromatography (eluent: a mixture ofethyl acetate and methanol at a ratio of 85:15). Each of the positionisomers was recrystallized from a mixed solvent of chloroform anddiethyl ether to give 1.37 g of2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(255) and 1.19 g of2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(256).

Properties of Compound (255):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.77(2H, d, J=4.8 Hz), 5.48(2H, s),7.09(2H, d, J=8.7 Hz), 7.22(1H, dd, J=7.2 and 4.9 Hz), 7.33(1H, d, J=7.8Hz), 7.66-7.70(2H, m), 7.73(1H, dd, J=8.4 and 1.5 Hz), 7.78(1H, d, J=8.4Hz), 7.91(1H, d, J=1.2 Hz), 8.15-8.19(2H, m), 8.56(1H, d, J=4.6 Hz).

IR(KBr): 1652 cm⁻¹.

mp: 116.1-119.1° C.

Properties of Compound (256):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 4.79(2H, d, J=4.8 Hz), 5.46(2H, s),7.17-7.24(4H, m), 7.35(1H, d, J=7.8 Hz), 7.69(2H, dt, J=7.6 and 1.7 Hz),7.83(1H, d, J=8.4 Hz), 8.19(2H, d, J=8.6 Hz), 8.26(1H, d, J=1.3 Hz),8.57(1H, d, J=4.8 Hz)

IR(KBr): 1634 cm⁻¹.

mp: 203.7-206.3° C.

EXAMPLES 195 AND 196 Synthesis of2-methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(257) and2-methyl-1-(2-phenylethyl)-5-(2-pyridylmethyl)carbamoyl]benzimidazole(258)

In the same manner as in Examples 193 and 194, 0.30 g of2-Methyl-1-(2-phenylethyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(257) and 0.23 g of2-methyl-1-(2-phenylethyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(258) were formed from 2.00 g of2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole and 15.0 g ofphenetyl iodide.

Properties of Compound (257):

¹ H-NMR(CDCl₃, δ): 2.17(3H, s), 3.10(2H, t, J=6.8 Hz), 4.35(2H, t, J=6.8Hz), 4.82(2H, d, J=4.8 Hz), 6.92-6.97(2H, m), 7.21-7.28(4H, m), 7.38(1H,d, J=7.8 Hz), 7.78(1H, br t), 7.68-7.73(3H, m), 7.98(1H, d, J=0.9 Hz),8.60(1H, dd, J=1.0 and 4.9 Hz).

IR(neat): 1633 cm⁻¹.

liquid.

Properties of Compound (258):

¹ H-NMR(CDCl₃, δ): 2.19(3H, s), 3.08(2H, t, J=6.8 Hz), 4.35(2H, t, J=6.8Hz), 4.81(2H, d, J=4.8 Hz), 6.91-6.96(2H, m), 7.19-7.26(4H, m), 7.31(1H,d, J=8.4 Hz), 7.36(1H, d, J=7.8 Hz), 7.64-7.73(2H, m), 7.85(1H, dd,J=1.7 and 8.4 Hz), 8.19(1H, d, J=1.3 Hz), 8.58(1H, d, J=4.0 Hz).

IR(neat): 1643 cm⁻¹.

liquid.

EXAMPLES 197 AND 198 Synthesis of1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(259) and1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(260)

In the same manner as in Examples 193 and 194, 0.25 g of1-(2,4-difluorobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(259) and 0.25 g of1-(2,4-difluorobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(260) were formed from 1.00 g of2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole and 1.00 g of2,4-difluorobenzyl bromide.

Properties of Compound (259):

¹ H-NMR(CDCl₃, δ): 2.62(3H, s), 4.78(2H, d, J=4.7 Hz), 5.38(2H, s),6.73-6.79(2H, m), 6.88(1H, t, J=10.0 Hz), 7.24(1H, dd, J=7.3 and 5.1Hz), 7.35(1H, d, J=7.8 Hz), 7.67-7.76(4H, m), 7.97(1H, s), 8.58(1H, d,J=4.4 Hz). IR(KBr): 1642 cm⁻¹.

mp: 98.0-104.0° C.

Properties of Compound (260):

¹ H-NMR(CDCl₃, δ): 2.62(3H, s), 4.79(2H, d, J=4.7 Hz), 5.35(2H, s),6.72-6.81(2H, m), 6.89(1H, t, J=9.8 Hz), 7.22(1H, t, J=6.2 Hz), 7.28(1H,d, J=8.4 Hz), 7.34(1H, d, J=7.8 Hz), 7.63-7.71(2H, m), 7.83(1H, d, J=8.4Hz), 7.97(1H, s), 8.57(1H, d, J=4.7 Hz).

IR(KBr): 1647 cm⁻¹.

mp: 143.5-144.0° C.

EXAMPLES 199 AND 200 Synthesis of1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(261) and1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(262)

Thirty milliliters of methanol and 0.20 g of 5% palladium on carbon wereadded to 2.32 g of a mixture of2-methyl-1-(4-nitrobenzyl)-6-[(2-pyridylmethyl)carbamoyl]benzimidazoleand2-methyl-1-(4-nitrobenzyl)-5-[(2-pyridylmethyl)carbamoyl]benzimidazole,and the mixture was stirred in a hydrogen atmosphere at room temperatureuntil the starting material disappeared. The solid material wasseparated through filtration, and the filtrate was concentrated. Theresulting residue was purified through medium-pressure silica-gel columnchromatography (eluent: a mixture of ethyl acetate and methanol at aratio of 85:15) to separate1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazoleand1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole.Each of these compounds was crystallized from a mixed solvent ofchloroform and diethyl ether. The crystals were separated throughfiltration, and were dried to give 0.354 g of1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(261) and 0.330 g of1-(4-aminobenzyl)-2-methyl-5-[(2-pyridylmethyl)carbamoyl]benzimidazole(262).

Properties of Compound (261):

¹ H-NMR(CDCl₃, δ): 3.00(3H, s), 4.98(2H, s), 5.88(2H, s), 7.55(2H, d,J=8.6 Hz), 7.69(2H, d, J=8.6 Hz), 7.90(1H, d, J=8.6 Hz), 7.96(1H, dt,J=7.1 and 0.6 Hz), 8.12(1H, J=8.0 Hz), 8.18(1H, dd, J=8.5 and 1.4 Hz),8.55(1H, dt, J=8.0 and 1.7 Hz), 8.62(1H, d, J=1.1 Hz), 8.77(1H, dd,J=5.9 and 1.1 Hz).

IR(KBr): 1643 cm⁻¹.

mp: 180.0-181.0° C.

Properties of Compound (262):

¹ H-NMR(CDCl₃, δ): 3.00(3H, s), 5.01(2H, s), 5.83(2H, s), 7.47(2H, d,J=8.5 Hz), 7.78(2H, d, J=8.5 Hz), 7.78(1H, d, J=8.9 Hz), 7.97(1H, dt,J=7.2 and 0.7 Hz), 8.13(1H, J=8.1 Hz), 8.15(1H, d, J=8.9 Hz), 8.51(1H,s), 8.55(1H, dt, J=7.9 and 1.6 Hz), 8.77(1H, d, J=5.8 Hz).

IR(KBr): 1639, 1612 cm⁻¹.

mp: 168.0-171.0° C.

EXAMPLE 201 Synthesis of1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(263)

Triethylamine (0.185 g) and benzenesulfonyl chloride (0.210 g) wereadded to a solution of 0.340 g of1-(4-aminobenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazolein 10 ml of chloroform, and the mixture was stirred at room temperaturefor 8 hours. Water was added thereto to stop the reaction, and thereaction mixture was extracted with chloroform. The organic layer waswashed three times with water, dried, and concentrated. The residue wasthen purified through silica-gel column chromatography (eluent: amixture of ethyl acetate and methanol at a ratio of 100:1 to 4:1) togive 0.300 g of1-[4-(benzenesulfonylamino)benzyl]-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole(263).

Properties of Compound (263):

¹ H-NMR(CDCl₃, δ): 2.53(3H, s), 4.78(2H, d, J=4.8 Hz), 5.28(2H, s),6.90(2H, t, J=8.6 Hz), 6.99(2H, d, J=8.5 Hz), 7.11(1H, s), 7.23(1H, dd,J=5.5 and 7.2 Hz), 7.34(1H, d, J=7.7 Hz), 7.40(2H, t, J=8.1 Hz),7.50(1H, t, J=7.5 Hz), 7.66-7.74(6H, m), 7.92(1H, s), 8.56(1H, d, J=4.8Hz).

IR(KBr): 1642 cm⁻¹.

mp: 204.4-206.5° C.

EXAMPLE 202 Synthesis of6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(264)

To a solution of 0.667 g of benzenesulfonic acid amide in 5 ml ofN,N-dimethylformamide were added 0.127 g of 60% sodium hydride at roomtemperature, and the mixture was stirred for 1 hour. Further, 0.648 g of1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole hydrochloridewere added thereto, and the mixture was stirred at room temperature for18 hours. Water was added to the reaction solution to stop the reaction,and the solvent was distilled off under reduced pressure. The residuewas extracted with ethyl acetate and with water. The organic layer wasconcentrated, and was purified through silica-gel column chromatography(eluent: ethyl acetate) to give 0.240 g of6-benzenesulfonylaminomethyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(264).

Properties of Compound (264):

¹ H-NMR(DMSO-d6, δ): 2.42(3H, s), 4.02(2H, m), 4.02(2H, m), 5.44(2H, s),6.36(1H, d, J=7.7 Hz), 7.03(1H, d, J=8.4 Hz), 7.18(1H, s), 7.21(1H, t),7.33(1H, t), 7.59-7.43(5H, m), 7.73(2H, d, J=7.5 Hz), 8.08(1H, s).

IR(KBr): 1522 cm⁻¹.

mp: 164.5-167.0° C.

EXAMPLE 203 Synthesis of1-(biphenyl-4-ylmethyl)-2-methyl-6-[(2-pyridylmethyl)aminomethyl]benzimidazole(265)

2-Aminomethylpyridine (0.372 g) was added to a solution of 0.597 g of1-(biphenyl-4-ylmethyl)-6-chloromethyl-2-methylbenzimidazole and 0.350 gof potassium carbonate in 3 ml of N,N-dimethylformamide, and the mixturewas stirred at 60° C. for 2 hours. The reaction mixture was extractedwith water and with ethyl acetate. The organic layer was washed twicewith water, and the solvent was distilled off under reduced pressure.The resulting residue was purified through silica-gel columnchromatography (eluent: a mixture of chloroform and methanol at a ratioof 9:1), and was recrystallized from a mixed solvent of ethyl acetateand hexane to give 0.300 g of1-(biphenyl-4-ylmethyl)-2-methyl-6-[2-pyridylmethyl)aminomethyl]benzimidazole(265).

Properties of Compound (265):

¹ H-NMR(CDCl₃, δ): 2.57(3H, s), 3.91(2H, s), 3.93(2H, s), 5.35(2H, s),7.08-7.14(3H, m), 7.23(2H, d, J=7.3 Hz), 7.30-7.35(2H, m), 7.41(2H, t),7.50-7.55(4H, m), 7.57(1H, dt, J=1.8 and 7.6 Hz), 7.68(1H, d, J=8.1 Hz),8.53(1H, d, J=4.9 Hz).

IR(KBr): 1618 cm⁻¹.

mp: 104.5-106.0° C.

EXAMPLE 204 Synthesis ofN-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazole-6-yl]propionamide(266)

5% Palladium on carbon (0.500 g) was added to a solution of 0.607 g ofN-benzenesulfonyl-1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acrylamidein 150 ml of ethanol, and the mixture was stirred in a hydrogenatmosphere at room temperature for 43 hours. The solid material wasseparated through filtration, and the filtrate was concentrated. Theresidue was dissolved in a mixed solution of a 20% potassiumhydrogencarbonate aqueous solution and methanol, and was adjusted to apH of from 5 to 6 with 10% hydrochloric acid. The crystals precipitatedwere separated through filtration, and was dried to give 0.250 g ofN-benzenesulfonyl-3-[1-(2-chlorobenzyl)-2-methylbenzimidazol-6-yl]propionamide(266).

Properties of Compound (266):

¹ H-NMR(DMSO-d6, δ): 2.45(3H, s), 2.52(2H, t), 2.78(2H, t), 5.37(2H, s),6.88(1H, d, J=8.4 Hz), 7.08(2H, d, J=7.4 Hz), 7.22-7.34(3H, m), 7.36(1H,t, J=8.1 Hz), 7.55(2H, t), 7.67(1H, t), 7.84(2H, d, J=7.6 Hz), 12.04(1H,br s).

IR(KBr): 1715 cm⁻¹.

Mass(FAB): m/e 468(M+1).

mp: 229.8-233.0° C.

EXAMPLE 205 Synthesis of6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole(267)

In the same manner as in Example 183, 0.279 g of6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(1,2,3-thiadiazol-4-yl)benzyl]benzimidazole(267) were formed from 0.382 g ofN-benzenesulfonyl-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide.

Properties of Compound (267):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.62(2H, s), 7.28(2H, d, J=8.2 Hz),7.58-7.63(3H, m), 7.67(1H, t, J=7.3 Hz), 7.74(1H, dd, J=8.5 and 1.2 Hz),7.99(2H, dd, J=8.4 and 1.2 Hz), 8.10(2H, d, J=8.2 Hz), 8.19(1H, s),9.58(1H, s), 12.47(1H, s).

IR(KBr): 1617, 1556 cm⁻¹.

mp: 258.5-260.0° C.(decomp.).

EXAMPLE 206 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(8-quinolinesulfonylcarbamoyl)benzimidazolesodium salt (268)

In the same manner as in Example 141, 0.400 g of1-(2-chlorobenzyl)-2-methyl-6-(8-quinolinesulfonylcarbamoyl)benzimidazolesodium salt (268) were formed from 0.450 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.485 g ofN,N'-carbonyldiimidazole, 0.625 g of 8-quinolinesulfonamide and 0.457 gof diazabicycloundecene.

Properties of Compound (268):

¹ H-NMR(DMSO-d6, δ): 2.42(3H, s), 5.48(2H, s), 6.32(1H, d, J=7.7 Hz),7.17(1H, t, J=7.5 Hz), 7.30(1H, t, J=7.7 Hz), 7.42(1H, d, J=8.4 Hz),7.48(1H, dd, J=4.2 and 8.2 Hz), 7.53(1H, d, J=8.0 Hz), 7.64(1H, t, J=7.7Hz), 7.79(1H, d, J=8.5 Hz), 7.88(1H, s), 8.04(1H, d, J=8.1 Hz),8.33-8.37(2H, m), 8.85(1H, dd)..

IR(KBr): 1594 cm⁻¹.

Mass(FAB): m/e 513(M+1).

mp: 348-352° C. (decomp.).

EXAMPLE 207 Synthesis of6-(4-tert-butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazolesodium salt (269)

In the same manner as in Example 141, 0.280 g of6-(4-tert-butylbenzenesulfonylcarbamoyl)-1-(2-chlorobenzyl)-2-methylbenzimidazolesodium salt (269) were obtained from 0.450 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.486 g ofN,N'-carbonyldiimidazole, 0.640 g of 2-tert-benzenesulfonamide and 0.657g of diazabicycloundecene.

Properties of Compound (269):

¹ H-NMR(DMSO-d6, δ) 1.25(9H, s), 2.46(3H, s), 5.51(2H, s), 6.37(1H, d,J=7.7 Hz), 7.18(1H, t), 7.31(1H, t), 7.34(2H, d, J=8.4 Hz), 7.44(1H, d,J=8.4 Hz), 7.54(1H, d, J=8.0 Hz), 7.69(2H, d, J=8.5 Hz), 7.78-7.82(2H,m).

IR(KBr): 1596 cm⁻¹.

Mass(FAB): m/e 518(M+1).

mp: 359.5-362° C.

EXAMPLE 208 Synthesis of6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole(270)

In the same manner as in Production Example 32, 0.30 g of crudeN-benzenesulfonyl-4-acetylamino-3-[4-(trifluoromethyl)benzylamino]benzamidewere obtained from 0.50 g ofN-benzenesulfonyl-4-acetylamino-3-aminobenzamide and 0.418 g of4-(trifluoromethyl)benzyl bromide. When this crude product was dissolvedin methanol and was allowed to stand, the crystals were precipitated.The crystals were separated through filtration, and were dried to give0.160 g of6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole(270).

Properties of Compound (270):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 5.66(2H, s), 7.28(2H, d, J=8.1 Hz),7.59-7.65(3H, m), 7.67-7.75(4H, m), 7.99(2H, d, J=7.5 Hz), 8.14(1H, d,J=1.0 Hz), 12.43(1H, s).

IR(KBr): 1618, 1550 cm⁻¹.

mp: 278.5-280.0° C.

EXAMPLE 209 Synthesis of 2-benzyl-6-carboxy-1-methylbenzimidazolehydrochloride (271)

A 5% sodium hydroxide aqueous solution (2.8 g) was added to a solutionof 0.340 g of 2-benzyl-6-ethoxycarbonyl-1-methylbenzimidazole in 4 ml ofethanol, and the mixture was heat-refluxed for 1.5 hours. The reactionmixture was acidified with 1-N hydrochloric acid, and was concentratedunder reduced pressure. Ethanol was added to the residue to extract theorganic substance. Ethanol was distilled off under reduced pressure togive 0.300 g of 2-benzyl-6-carboxy-1-methylbenzimidazole hydrochloride(271).

Properties of Compound (271):

¹ H-NMR(DMSO-d6, δ): 4.00(3H, s), 4.62(2H, s), 7.33(1H, m),7.35-7.45(4H, m), 7.83(1H, d, J=8.4 Hz), 8.06(1H, d, J=8.4 Hz), 8.42(1H,s), 13.3(1H, br s).

EXAMPLE 210 Synthesis of5-benzenesulfonylcarbamoyl-2-methylbenzimidazole (272)

A mixture of 0.500 g ofN-benzenesulfonyl-4-acetylamino-3-aminobenzamide, 3.9 g of 35%hydrochloric acid, 15 ml of methanol and 12 ml of water was stirred at60° C. for 1 hour. The reaction mixture was neutralized with a potassiumhydrogencarbonate aqueous solution. The crystals precipitated wereseparated through filtration, and were dried to give 0.404 g of5-benzenesulfonylcarbamoyl-2-methylbenzimidazole (272).

Properties of Compound (272):

¹ H-NMR(DMSO-d6, δ): 2.79(3H, s), 7.64-7.68(2H, m), 7.72-7.76(1H, m),7.81(1H d, J=8.7 Hz), 7.94(1H, dd, J=1.6 and 8.7 Hz), 8.02-8.05(2H, m),8.30(1H, s).

IR(KBr): 1701 cm⁻¹.

mp: 223.0-227.5° C.

PRODUCTION EXAMPLE 45 Production of ethyl3-methoxyacetylamino-4-nitrobenzoate

Ethyl 3-methoxyacetylamino-4-nitrobenzoate (18.7 g) was obtained from15.0 g of ethyl 3-amino-4-nitrobenzoate and 15.0 g of methoxyacetylchloride in the same manner as in Production Example 12.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.42(3H, t, J=7.2 Hz), 3.58(3H, s), 4.11(2H, s),4.43(2H, q, J=7.2 Hz), 7.85(1H, dd, J=1.6 and 8.7 Hz), 8.27(1H, d, J=8.7Hz), 9.44(1H, d, J=1.6 Hz), 11.15(1H, s).

EXAMPLE 211 Synthesis of1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(273)

Crude ethyl3-[N-(biphenyl-4-ylmethyl)methoxyacetylamino]-4-nitrobenzoate (2.02 g)was obtained from 2.00 g of ethyl 3-methoxyacetylamino-4-nitrobenzoateand 2.98 g of 4-biphenylmethyl bromide in the same manner as inProduction Example 14. Subsequently, 1.44 g of crude1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(273) were obtained in the same manner as in Example 24.

EXAMPLE 212 Synthesis of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole (274)

In the same manner as in Example 53, 0.864 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole (274)were formed from 1.44 g of crude1-(biphenyl-4-ylmethyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole.

Properties of Compound (274):

¹ H-NMR(DMSO-d6, δ): 3.35(3H, s), 4.77(2H, s), 5.68(2H, s), 7.25(2H, d,J=8.3 Hz), 7.35(1H, t, J=7.4 Hz), 7.44(2H, t, J=7.5 Hz), 7.61-7.66(4H,m), 7.74(1H, d, J=8.6 Hz), 7.83(1H, dd, J=1.6 and 8.5 Hz), 8.08(1H, d,J=1.2 Hz), 12.83(1H, s).

EXAMPLE 213 Synthesis of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole(275)

In the same manner as in Example 98, 0.429 g of1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole(275) were formed from 0.400 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-methoxymethylbenzimidazole, 0.348 gof N,N'-carbonyldiimidazole, 0.294 g of 1-butanesulfonamide and 0.327 gof diazabicycloundecene.

Properties of Compound (275):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.4 Hz), 1.35-1.42(2H, m),1.62-1.70(2H, m), 3.33(3H, s), 3.51(2H, t, J=7.6 Hz), 4.74(2H, s),5.65(2H, s), 7.26(2H, d, J=8.3 Hz), 7.35(1H, t, J=7.3 Hz), 7.44(2H, t,J=7.5 Hz), 7.62-7.67(4H, m), 7.78(1H, d, J=8.6 Hz), 7.84(1H, dd, J=1.5and 8.4 Hz), 8.24(1H, d, J=1.5 Hz), 12.01(1H, s).

IR(KBr): 1684 cm⁻¹.

mp: 176.0-178.5° C.

EXAMPLE 214 Synthesis of1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(276)

Crude ethyl 3-[N-4-benzyloxybenzyl)methoxyacetylamino]-4-nitrobenzoate(2.14 g) was obtained from 2.00 g of ethyl3-methoxyacetylamino-4-nitrobenzoate and 3.30 g of 4-benzyloxybenzylchloride in the same manner as in Production Example 14. Subsequently,1.66 g of crude1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(276) were obtained in the same manner as in Example 24.

EXAMPLE 215 Synthesis of1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole (277)

In the same manner as in Example 53, 2.64 g of1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole (277) wereformed from 3.75 g of crude1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole.

Properties of Compound (277):

¹ H-NMR(DMSO-d6, δ): 3.34(3H, s), 4.74(2H, s), 5.05(2H, s), 5.53(2H, s),6.97(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.7 Hz), 7.31(1H, t, J=7.2 Hz),7.41(2H, d, J=7.2 Hz), 7.71(1H, d, J=8.4 Hz), 7.81(1H, dd, J=1.5 and 7.4Hz), 8.04(1H, d, J=1.1 Hz), 12.81(1H, s).

EXAMPLE 216 Synthesis of1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole(278)

In the same manner as in Example 155, 0.321 g of1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methoxymethylbenzimidazole(278) were formed from 0.400 g of1-(4-benzyloxybenzyl)-6-carboxy-2-methoxymethylbenzimidazole, 0.322 g ofN,N'-carbonyldiimidazole, 0.272 g of 1-butanesulfonamide and 0.302 g ofdiazabicycloundecene.

Properties of Compound (278):

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.4 Hz), 1.37-1.44(2H,m),1.65-1.71(2H, m), 3.32(3H, s), 3.52(2H, t, J=7.6 Hz), 4.71(2H, s),5.05(2H, s), 5.51(2H, s), 6.98(2H, d, J=8.7 Hz), 7.15(2H, d, J=8.3 Hz),7.31(1H, t, J=7.2 Hz), 7.37(2H, t, J=7.2 Hz), 7.41(2H, d, J=7.1 Hz),7.74(1H, d, J=8.5 Hz), 7.82(1H, dd, J=1.5 and 8.5 Hz), 8.21(1H, s),11.98(1H, s).

IR(KBr): 1685 cm⁻¹.

mp: 72.0-74.0° C.

EXAMPLE 217 Synthesis of1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(279)

Crude ethyl 3-[N-2,4-dichlorobenzyl)methoxyacetylamino]-4-nitrobenzoatewas obtained from 2.00 g of ethyl 3-methoxyacetylamino-4-nitrobenzoateand 2.08 g of 2,4-dichlorobenzyl chloride in the same manner as inProduction Example 14. Subsequently, 3.15 g of crude1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole(279) were obtained in the same manner as in Example 24.

EXAMPLE 218 Synthesis of6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole (280)

In the same manner as in Example 53, 1.46 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole (280) wereformed from 3.15 g of crude1-(2,4-dichlorobenzyl)-6-ethoxycarbonyl-2-methoxymethylbenzimidazole.

Properties of Compound (280):

¹ H-NMR(DMSO-d6, δ): 3.23(3H, s), 4.70(2H, s), 5.68(2H, s), 6.54(1H, d,J=8.5 Hz), 7.31(1H, dd, J=2.2 and 8.5 Hz), 7.73(1H, d, J=2.1 Hz),7.76(1H, d, J=8.5 Hz), 7.86(1H, dd, J=1.5 and 8.5 Hz), 8.00(1H, d, J=1.1Hz), 12.85(1H, s).

EXAMPLE 219 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole(281)

In the same manner as in Example 98, 0.430 g of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole(281) were formed from 0.400 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methoxymethylbenzimidazole, 0.355 gof N,N'-carbonyldiimidazole, 0.300 g of 1-butanesulfonamide and 0.333 gof diazabicycloundecene.

Properties of Compound (281):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.3 Hz), 1.37-1.42(2H, m),1.63-1.69(2H, m), 3.21(3H, s), 3.51(2H, t, J=7.6 Hz), 4.68(2H, s),5.65(2H, s), 6.46(1H, d, J=8.5 Hz), 7.31(1H, dd, J=2.0 and 8.4 Hz),7.75(1H, d, J=2.1 Hz), 7.80(1H, d, J=8.5 Hz), 7.86(1H, dd, J=1.7 and 8.6Hz), 8.14(1H, d, J=1.2 Hz), 12.00(1H, s).

IR(KBr): 1694 cm⁻¹.

mp: 168.5-170.5° C.

EXAMPLE 220 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)benzimidazole(282)

In the same manner as in Example 98, 0.459 g of1-(2-chlorobenzyl)-2-methyl-6-(1-propanesulfonylcarbamoyl)benzimidazole(282) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.328 g of 1-propanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (282):

¹ H-NMR(DMSO-d6, δ): 0.98(3H, t, J=7.4 Hz), 1.67-1.75(2H, m), 2.50(3H,s), 3.49(2H, t, J=7.7 Hz), 5.61(2H, s), 6.45(1H, d, J=7.0 Hz), 7.24(1H,dt, J=0.8 and 7.8 Hz), 7.35(1H, dt, J=1.4 and 7.4 Hz), 7.63(1H, dd,J=0.9 and 7.9 Hz), 7.69(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.6 and 8.5Hz), 8.12(1H, d, J=1.6 Hz), 11.90(1H, s).

IR(KBr): 1676 cm⁻¹.

mp: 217.5-218.5° C.

EXAMPLE 221 Synthesis of6-ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (283)

In the same manner as in Example 98, 0.459 g of6-ethanesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (283)were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.290 g of ethanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (283):

¹ H-NMR(DMSO-d6, δ): 1.23(3H, t, J=7.3 Hz), 2.50(3H, s), 3.50(2H, q,J=7.3 Hz), 5.61(2H, s), 6.45(1H, d, J=6.7 Hz), 7.24(1H, dt, J=0.9 and7.5 Hz), 7.35(1H, dt, J=1.4 and 7.5 Hz), 7.58(1H, dd, J=1.0 and 8.0 Hz),7.69(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.6 and 8.4 Hz), 8.13(1H, d, J=1.5Hz), 11.86(1H, s).

IR(KBr): 1673 cm⁻¹.

mp: 256.5-258.5° C.

EXAMPLE 222 Synthesis of6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(284)

In the same manner as in Example 98, 0.323 g of6-(propanesultam-1-ylcarbonyl)-1-(2-chlorobenzyl)-2-methylbenzimidazole(284) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.420 g of 1-(3-chloropropane)sulfonamide and0.404 g of diazabicycloundecene.

Properties of Compound (284):

¹ H-NMR(DMSO-d6, δ): 2.27-2.33(2H, m), 2.52(3H, s), 3.52(2H, t, J=7.0Hz), 3.87(2H, t, J=6.6 Hz), 5.59(2H, s), 6.57(1H, d, J=7.7 Hz), 7.23(1H,t, J=7.6 Hz), 7.34(1H, t, J=6.4 Hz), 7.53-7.58(2H, m), 7.67(1H, d, J=8.4Hz), 7.79(1H, d, J=l.1Hz).

IR(KBr): 1648 cm⁻¹.

mp: 165.5-166.6° C.

EXAMPLE 223 Synthesis of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropylbenzimidazolepotassium salt (285)

In the same manner as in Example 170, 0.196 g of6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-cyclopropylbenzimidazolepotassium salt (285) were obtained from 0.400 g ofN-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide and0.101 g of cyclopropanecarbonyl chloride viaN-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-cyclopropanecarbonylaminobenzamide.

Properties of Compound (285):

¹ H-NMR(DMSO-d6, δ):1.00-1.15(4H, m), 2.23-2.31(1H, m), 5.66(2H, s),7.21(2H, m, J=9.1 Hz), 7.32-7.45(7H, m), 7.59-7.63(4H, m), 7.78-7.83(3H,m), 7.97(1H, s).

IR(Nujol): 1540 cm⁻¹.

Mass(FAB): m/e 546(M+1).

mp: 220.8-224.8° C.

EXAMPLE 224 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(286)

In the same manner as in Example 98, 0.491 g of1-(2-chlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(286) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.402 g of 1-pentanesulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (286):

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.2 Hz), 1.23-1.28(2H, m),1.32-1.37(2H, m), 1.65-1.69(2H, m), 3.50(2H, t, J=7.8 Hz), 5.61(2H, s),6.45(1H, d, J=7.5 Hz), 7.24(1H, t, J=7.6 Hz), 7.35(1H, t, J=7.5 Hz),7.57(1H, d, J=7.9 Hz), 7.69(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.7 and 8.4Hz), 8.12(1H, d, J=1.2 Hz), 12.25(1H, s).

IR(KBr): 1684 cm⁻¹.

mp: 173.3-179.8° C.

EXAMPLE 225 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]benzimidazole(287)

In the same manner as in Example 98, 0.284 g of1-(2-chlorobenzyl)-2-methyl-6-[(3-methylbutane)sulfonylcarbamoyl]benzimidazole(287) were formed from 0.300 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.323 g ofN,N-carbonyldiimidazole, 0.302 g of 1-(3-methyl)butanesulfonamide and0.303 g of diazabicycloundecene.

Properties of Compound (287):

¹ H-NMR(DMSO-d6, δ): 0.84(6H, d, J=6.5 Hz), 1.52-1.59(2H, m),1.61-1.70(1H, m), 3.44(2H, t, J=7.9 Hz), 5.60(2H, s), 6.45(1H, d, J=7.8Hz), 7.24(1H, t, J=7.6 Hz), 7.35(1H, t, J=7.4 Hz), 7.57(1H, d, J=7.9Hz), 7.66(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.6 and 8.6 Hz), 8.09(1H, s),11.87(1H, s).

IR(KBr): 1682 cm⁻¹.

mp: 201.0-204.1° C.

EXAMPLE 226 Synthesis of1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole(288)

In the same manner as in Example 98, 0.379 g of1-(2-chlorobenzyl)-6-(1-hexanesulfonylcarbamoyl)-2-methylbenzimidazole(288) were formed from 0.300 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.323 g ofN,N-carbonyldiimidazole, 0.335 g of 1-hexanesulfonamide and 0.303 g ofdiazabicycloundecene.

Properties of Compound (288):

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.0 Hz), 1.18-1.28(4H, m),1.32-1.41(2H, m), 1.63-1.71(2H, m), 2.53(3H, s), 3.50(2H, t, J=7.7 Hz),5.64(2H, s), 6.51(1H, d, J=7.7 Hz), 7.25(1H, dt, J=1.2 and 7.8 Hz),7.36(1H, dt, J=1.4 and 7.7 Hz), 7.58(1H, dd, J=1.0 and 8.0 Hz), 7.72(1H,d, J=8.5 Hz), 7.84(1H, dd, J=1.6 and 8.5 Hz), 8.15(1H, d, J=1.3 Hz),11.87(1H, s).

IR(KBr): 1682 cm⁻¹.

mp: 141.2-143.5° C.

EXAMPLE 227 Synthesis of6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole(289)

In the same manner as in Example 18, 0.760 g of6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole(289) were formed from 1.01 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1 ml ofdiphenylphosphorylazide, 1 ml of diisopropylethylamine and 25 ml oftert-butyl alcohol.

Properties of Compound (289):

¹ H-NMR(CDCl₃, δ): 1.49(9H, S), 2.47(3H, s), 5.37(2H, s), 6.41(1H, d,J=7.5 Hz), 6.55(1H, br s), 6.93(1H, dd, J=1.9 and 8.6 Hz), 7.08(1H, t,J=7.5 Hz), 7.22(1H, t), 7.44(1H, d, J=8.0 Hz), 7.62(2H, d, J=8.6 Hz).

EXAMPLE 228 Synthesis of6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole (290)

In the same manner as in Example 22, 0.420 g of6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole (290) were formed from0.760 g of6-tert-butoxycarbonylamino-1-(2-chlorobenzyl)-2-methylbenzimidazole.

Properties of Compound (290):

¹ H-NMR(DMSO-d6, δ): 2.37(3H, s), 4.83(2H, br s), 5.32(2H, s), 6.33(1H,d, J=1.9 Hz), 6.42(1H, d, J=7.7 Hz), 6.46(1H, dd, J=1.9 and 8.5 Hz),7.19-7.24(2H, m), 7.31(1H, t), 7.53(1H, d, J=7.9 Hz).

EXAMPLE 229 Synthesis of6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-2-methylbenzimidazole (291)

In the same manner as in Example 20, 0.230 g of6-(1-butanesulfonylamino)-1-(2-chlorobenzyl)-2-methylbenzimidazole (291)were formed from 0.300 g of6-amino-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.216 g of1-butanesulfonyl chloride and 0.130 g of triethylamine.

Properties of Compound (291):

¹ H-NMR(DMSO-d6, δ): 0.74(3H, m), 1.23(2H, m), 1.55(2H, m), 2.50(3H, s),2.89(2H, m), 5.47(2H, s), 6.58(1H, d, J=7.4 Hz). 7.02(1H, d, J=8.5 Hz),7.10(1H, s), 7.23(1H, t), 7.33(1H, t), 7.52(2H, m), 9.55(1H, s).

IR(KBr): 1629 cm⁻¹.

mp: 149.5-151.0° C.

PRODUCTION EXAMPLE 46 Production of methyl2-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate

In the same manner as in Production Example 14, 0.250 g of methyl2-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate were formed from1.00 g of methyl 2-acetylamino-3-nitrobenzoate and 0.985 g of2,4-dichlorobenzyl chloride.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.99(3H, s), 3.71(3H, s), 4.85(1H, d, J=4.5 Hz),4.98(1H, d, J=4.5 Hz), 7.17-7.22(2H, m), 7.46(1H, d, J=7.9 Hz), 7.63(1H,t, J=7.9 Hz), 7.98(1H, d, J=8.0 Hz), 8.09(1H, d, J=7.9 Hz).

EXAMPLE 230 Synthesis of1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole (292)

In the same manner as in Example 24, 5.15 g of1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole (292) wereformed from 6.50 g of methyl2-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate.

Properties of Compound (292):

¹ H-NMR(CDCl₃, δ): 2.53(3H, s), 3.70(3H, s), 5.72(2H, s), 6.26(1H, d,J=8.4 Hz), 7.04(1H, dd, J=2.0 and 8.4 Hz), 7.28(1H, t, J=7.9 Hz),7.45(1H, d, J=2.0 Hz), 7.75(1H, d, J=7.8 Hz), 7.93(1H, d, J=7.9 Hz).

EXAMPLE 231 Synthesis of7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (293)

In the same manner as in Example 53, 1.76 g of7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (293) were formedfrom 2.00 g of1-(2,4-dichlorobenzyl)-7-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (293):

¹ H-NMR(DMSO-d6, δ): 2.49(3H, s), 5.81(2H, s), 6.09(1H, d, J=8.4 Hz),7.21-7.28(2H, m), 7.62(1H, d, J=7.8 Hz), 7.67(1H, d, J=2.2 Hz), 7.83(1H,d, J=8.0 Hz), 13.04(1H, br s).

EXAMPLE 232 Synthesis of7-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(294)

In the same manner as in Example 98, 0.325 g of7-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(294) were formed from 0.463 g of7-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.448 g ofN,N'-carbonyldiimidazole, 0.379 g of 1-butanesulfonamide and 0.421 g ofdiazabicycloundecene.

Properties of Compound (294):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.3 Hz), 1.33(2H, m), 1.44(2H, m),2.53(3H, s), 3.16(2H, m), 5.64(2H, s), 6.03(1H, d, J=8.4 Hz), 7.25(1H,dd, J=2.1 and 8.4 Hz), 7.30(1H, t, J=7.8 Hz), 7.44(1H, d, J=7.4 Hz),7.68(1H, d, J=2.1 Hz), 7.87(1H, d, J=7.8 Hz), 12.18(1H, br s).

IR(KBr): 1690 cm⁻¹.

mp: 98.5-102.0° C.

EXAMPLE 233 Synthesis of1-(2-chlorobenzyl)-2-methyl-6-[1-[3-(trimethylsilyl)propane]sulfonylcarbamoyl]benzimidazole(295)

In the same manner as in Example 149, 0.604 g of1-(2-chlorobenzyl)-2-methyl-6-[1-[3-(trimethylsilyl)propane]sulfonylcarbamoyl]benzimidazole(295) were formed from 0.400 g of6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole, 0.431 g ofN,N'-carbonyldiimidazole, 0.520 g of1-[3-(trimethylsilyl)propane]sulfonamide and 0.404 g ofdiazabicycloundecene.

Properties of Compound (295):

¹ H-NMR(DMSO-d6, δ): -0.06(9H, s), 0.61(2H, t, J=8.6 Hz), 1.66-1.73(2H,m), 2.50(3H, s), 3.51(2H, t, J=7.7 Hz), 5.61(2H, s), 6.46(1H, d, J=7.8Hz), 7.24(1H, t, J=7.6 Hz), 7.35(1H, t, J=7.6 Hz), 7.57(1H, dd, J=7.9and 0.9 Hz), 7.70(1H, d, J=8.5 Hz), 7.81(1H, dd, J=1.5 and 8.5 Hz),8.12(1H, d, J=1.4 Hz), 11.98(1H, s).

IR(KBr): 1688 cm⁻¹.

mp: 197.0-203.9° C.

EXAMPLE 234 Synthesis of 4-ethoxycarbonyl-2-methylbenzimidazole (296)

A mixture of 8.03 g of methyl 2-acetylamino-3-nitrobenzoate, 18.8 g ofreduced iron, 20 ml of acetic acid and 40 ml of ethanol washeat-refluxed for 18 hours. After the solvent was concentrated,chloroform and 10% hydrochloric acid were added to the residue forextraction. The aqueous layer was acidified with a saturated aqueoussolution of sodium hydrogencarbonate, and was extracted with chloroform.Chloroform was then distilled off under reduced pressure to give 1.61 gof 4-ethoxycarbonyl-2-methylbenzimidazole (296).

Properties of Compound (296):

¹ H-NMR(CDCl₃, δ): 1.43(3H, t), 2.66(3H, s), 4.45(2H, q), 7.24-7.28(1H,m), 7.84-7.89(2H, m), 10.26(1H, br s).

EXAMPLE 235 Synthesis of1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole (297)

A mixture of 1.61 g of 4-ethoxycarbonyl-2-methylbenzimidazole, 3.08 g of2,4-dichlorobenzyl chloride, 1.51 g of potassium iodide, 1.05 g ofpotassium carbonate and 4 ml of N,N-dimethylformamide was stirred at 80°C. for 16 hours. The reaction mixture was extracted with chloroform andwith water. The chloroform layer was washed with water, dried, andconcentrated. The residue was purified through silica-gel columnchromatography (eluent: a mixture of hexane and ethyl acetate at a ratioof 2:8) to give 0.730 g of1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole (297).

Properties of Compound (297):

¹ H-NMR(CDCl₃, δ): 1.47(3H, t, J=7.1 Hz), 2.63(3H, s), 4.52(2H, q, J=7.1Hz), 5.39(2H, s), 6.30(1H, d, J=8.4 Hz), 7.06(1H, dd, J=2.1 and 8.4 Hz),7.25(1H, t, J=7.9 Hz), 7.32(1H, dd, J=1.0 and 7.9 Hz), 7.48(1H, d, J=2.0Hz), 7.93(1H, dd, J=1.0 and 7.7 Hz).

EXAMPLE 236 Synthesis of4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (298)

In the same manner as in Example 53, 0.575 g of4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (298) were formedfrom 0.730 g of1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (298):

¹ H-NMR(DMSO-d6, δ): 2.65(3H, s), 5.67(2H, s), 6.73(1H, d, J=8.3 Hz),7.33(1H, dd, J=2.2 and 8.4 Hz), 7.39(1H, t, J=7.9 Hz), 7.74(1H, d, J=2.2Hz), 7.76(1H, d, J=8.2 Hz), 7.85(1H, d, J=7.5 Hz).

EXAMPLE 237 Synthesis of4-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(299)

In the same manner as in Example 98, 0.275 g of4-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(299) were formed from 0.350 g of4-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.339 g ofN,N'-carbonyldiimidazole, 0.287 g of 1-butanesulfonamide and 0.318 g ofdiazabicycloundecene.

Properties of Compound (299):

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.3 Hz), 1.42(2H, m), 1.73(2H, m),2.61(3H, s), 3.61(2H, m), 5.65(2H, s), 6.67(1H, d, J=8.4 Hz), 7.32(1H,dd, J=2.1 and 8.4 Hz), 7.39(1H, t, J=7.9 Hz), 7.73(1H, d, J=2.1 Hz),7.78(1H, d, J=8.0 Hz), 7.91(1H, d, J=7.7 Hz), 12.66(1H, br s).

IR(KBr): 1699 cm⁻¹.

mp: 180.7-183.6° C.

EXAMPLE 238 Synthesis of1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (300)

In the same manner as in Production Example 14, crude ethyl3-[N-(4-benzyloxybenzyl)acetylamino]-4-nitrobenzoate was obtained from2.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 3.69 g of4-benzyloxybenzyl chloride. Subsequently, 4.09 g of crude1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (300) wereformed in the same manner as in Example 24.

EXAMPLE 239 Synthesis of1-(4-benzyloxybenzyl)-6-carboxy-2-methylbenzimidazole (301)

In the same manner as in Example 53, 1.13 g of1-(4-benzyloxybenzyl)-6-carboxy-2-methylbenzimidazole (301) were formedfrom 4.09 g of1-(4-benzyloxybenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (301):

¹ H-NMR(DMSO-d6, δ): 2.57(3H, s), 5.05(2H, s), 5.48(2H, s), 6.97(2H, d,J=8.6 Hz), 7.08(2H, d, J=8.5 Hz), 7.28-7.43(5H, m), 7.60(1H, d, J=8.3Hz), 7.78(1H, d, J=7.5 Hz), 8.07(1H, s), 12.72(1H, s).

EXAMPLE 240 Synthesis of1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(302)

In the same manner as in Example 149, 0.206 g of1-(4-benzyloxybenzyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(302) were formed from 0.300 g of6-carboxy-1-(4-benzyloxybenzyl)-2-methylbenzimidazole, 0.242 g ofN,N'-carbonyldiimidazole, 0.204 g of 1-butanesulfonamide and 0.227 g ofdiazabicycloundecene.

Properties of Compound (302):

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.3 Hz), 1.38-1.43(2H, m),1.64-1.71(2H, m), 2.54(3H, s), 3.49(2H, t, J=6.8 Hz), 5.05(2H, s),5.45(2H, s), 6.98(2H, d, J=8.7 Hz), 7.10(2H, d, J=8.7 Hz), 7.31(1H, t,J=7.2 Hz), 7.37(2H, t, J=7.2 Hz), 7.41(2H, d, J=7.3 Hz), 7.62(1H, d,J=8.5 Hz), 7.79(1H, dd, J=1.5 and 8.4 Hz), 8.23(1H, s), 11.93(1H, s).

IR(KBr): 1684 cm⁻¹.

mp: 132.4-137.7° C.

EXAMPLE 241 Synthesis of6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole(303)

In the same manner as in Production Example 14, 0.750 g of crude ethyl3-[N-[(2'-cyanobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate wereobtained from 1.00 g of ethyl 3-acetylamino-4-nitrobenzoate and 1.30 gof 4'-bromomethyl-2-cyanobiphenyl. Subsequently, 0.410 g of6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimicazole(303) were formed in the same manner as in Example 24.

Properties of Compound (303):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t), 2.63(3H, s), 4.39(2H, q), 5.46(2H, s),7.17(2H, d), 7.40-7.66(5H, m), 7.73-7.78(2H, m), 8.00(1H, dd, J=1.5 and8.5 Hz), 8.05(1H, d, J=1.2 Hz).

EXAMPLE 242 Synthesis of6-carboxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole (304)

In the same manner as in Example 53, 0.190 g of6-carboxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole (304)were formed from 0.410 g of6-ethoxycarbonyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole.

Properties of Compound (304):

¹ H-NMR(DMSO-d6, δ): 2.59(3H, s), 5.67(2H, s), 7.24(2H, d, J=8.1 Hz),7.53-7.64(5H, m), 7.75(1H, t, J=7.7 Hz), 7.80(1H, d), 7.92(1H, d, J=7.7Hz), 8.12(1H, s), 12.74(1H, br s).

EXAMPLE 243 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole(305)

In the same manner as in Example 155, 0.155 g of6-(1-butanesulfonylcarbamoyl)-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-methylbenzimidazole(305) were formed from 0.187 g of6-carboxy-1-[(2'-biphenyl-4-yl)methyl]-2-methylbenzimidazole, 0.160 g ofN,N'-carbonyldiimidazole, 0.135 g of 1-butanesulfonamide and 0.150 g ofdiazabicycloundecene by being purified through silica-gel columnchromatography (eluent: a mixture of chloroform and methanol at a ratioof 20:1).

Properties of Compound (305):

¹ H-NMR(DMSO-d6, δ): 0.83(3H, t, J=7.4 Hz), 1.34(2H, m), 1.60(2H,m),2.56(3H, s), 3.27(2H, m), 5.62(2H, s), 7.23(2H, d, J=8.2 Hz),7.53-7.57(4H, m), 7.60(1H, d, J=7.8 Hz), 7.75(1H, dt, J=1.0 and 7.8 Hz),7.83(1H, dd, J=1.5 and 8.4 Hz), 7.92(1H, d), 8.13(1H, s), 11.92(1H, brs).

IR(KBr): 2223 cm⁻¹.

mp: 115-118° C.

PRODUCTION EXAMPLE 47 Production of 2-fluoro-4'-methylbiphenyl

Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and asolution of 8.33 g of 4-bromotoluene in 30 ml of tetrahydrofuran wereadded in this order to 30 ml of tetrahydrofuran which had been cooled to-78° C. in a nitrogen atmosphere, and the mixture was then stirred at-78° C. for 1 hour. A solution containing 6.64 g of zinc chloride whichhad been dehydrated through heat-melting under reduced pressure in 30 mlof tetrahydrofuran was added thereto at -78° C., and the mixture wasstirred at room temperature for 1 hour. This solution was added to asolution of 7.22 g of 2-fluoroiodobenzene and 0.52 g oftetrakis(trifluorophosphine)palladium (O) in 30 ml of tetrahydrofuran atroom temperature, and the mixed solution was stirred for 24 hours. Thereaction solution was diluted with 300 ml of ethyl acetate, and thedilute solution was extracted with the addition of 10% hydrochloricacid. The organic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and then concentrated. The residue was purifiedthrough silica-gel column chromatography (eluent: hexane) to give 6.05 gof oily 2-fluoro-4'-methylbiphenyl.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.39(3H, s), 7.10-7.30(5H, m), 7.39-7.49(3H, m).

PRODUCTION EXAMPLE 48 Production of 2-fluoro-4'-bromomethylbiphenyl

A mixture of 8.70 g of 2-fluoro-4'-methylbiphenyl, 8.32 g ofN-bromosuccinimide, 0.10 g of 2,2'-azobisisobutylonitrile and 150 ml ofcarbon tetrachloride was heat-refluxed for 5 hours. The reactionsolution was washed with water, and the organic layer was concentrated.The resulting residue was purified through silica-gel columnchromatography (eluent: a mixture of hexane and ethyl acetate at a ratioof 9:1) to obtain crude 2-fluoro-4'-bromomethylbiphenyl. Further, thiscompound was crystallized from hexane to give 4.93 g of2-fluoro-4'-bromomethylbiphenyl.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 4.55(2H, s), 7.13-7.23(2H, m), 7.33(1H, m), 7.43(1H,m), 7.47(2H, d, J=8.1 Hz), 7.54(2H, d, J=8.1 Hz).

PRODUCTION EXAMPLE 49 Production of ethyl3-[N-[(2'-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate

Ethyl 3-[N-[2'-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate(1.90 g) was formed from 1.54 g of ethyl 3-acetylamino-4-nitrobenzoateand 2.26 g of 2-fluoro-4'-bromomethylbiphenyl in the same manner as inProduction Example 14.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.33(3H, t, J=7.1 Hz), 1.92(3H, s), 4.36(2H, m),4.44(1H, d, J=4.4 Hz), 5.32(1H, d, J=4.4 Hz), 7.13(1H, m), 7.18-7.22(3H,m), 7.31(1H, m), 7.40(1H, dt, J=1.6 and 7.7 Hz), 7.44(2H, d), 7.67(1H,d, J=1.6 Hz), 7.94(1H, d, J=8.4 Hz), 8.15(1H, dd, J=1.8 and 8.4 Hz).

EXAMPLE 244 Synthesis of6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(306)

In the same manner as in Example 24, 1.53 g of6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(306) were formed from 1.90 g of ethyl3-[N-[2'-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate.

Properties of Compound (306):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.62(3H, s), 4.38(2H, q, J=7.1Hz), 5.43(2H, s), 7.10-7.17(3H, m), 7.19(1H, dt, J=1.0 and 7.5 Hz),7.31(1H, m), 7.38(1H, dt, J=1.8 and 7.8 Hz), 7.50(2H, dd), 7.74(1H, d,J=8.5 Hz), 8.00(1H, dd, J=1.4 and 8.4 Hz), 8.06(1H, s).

EXAMPLE 245 Synthesis of6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (307)

In the same manner as in Example 53, 1.24 g of6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (307)were formed from 1.50 g of6-ethoxycarbonyl-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole.

Properties of Compound (307):

¹ H-NMR(DMSO-d6, δ): 2.59(3H, s), 5.63(2H, s), 7.19(2H, d, J=8.1 Hz),7.24-7.31(2H, m), 7.39(1H, m), 7.46-7.53(3H, m), 7.62(1H, d, J=8.4 Hz),7.80(1H, dd, J=1.3 and 8.4 Hz), 8.10(1H, s).

EXAMPLE 246 Synthesis of6-(1-ethanesulfonylcarbamoyl)-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(308)

In the same manner as in Example 98, 0.340 g of6-(1-ethanesulfonylcarbamoyl)-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(308) were formed from 0.455 g of6-carboxy-1-[(2'-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,0.409 g of N,N'-carbonyldiimidazole, 0.346 g of 1-butanesulfonamide and0.384 g of diazabicycloundecene.

Properties of Compound (308):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.3 Hz), 1.39(1H, m), 1.67(1H, m),2.57(3H, s), 3.51(1H, t), 5.60(2H, s), 7.21(2H, d, J=8.0 Hz),7.24-7.30(2H, m), 7.39(1H, m), 7.48(1H, t), 7.52(2H, d, J=8.0 Hz),7.66(1H, d, J=8.5 Hz), 7.80(1H, d, J=8.5 Hz), 8.25(1H, s), 11.93(1H, brs).

PRODUCTION EXAMPLE 50 Production of 3-fluoro-4-methylbiphenyl

Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and asolution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml oftetrahydrofuran were added in this order to 30 ml of tetrahydrofuranwhich had been cooled to -78° C. in a nitrogen atmosphere, and themixture was then stirred at -78° C. for 1 hour. A solution containing6.64 g of zinc chloride which had been dehydrated through heat-meltingunder reduced pressure in 30 ml of tetrahydrofuran was added thereto at-78° C., and the mixture was stirred at room temperature for 1 hour. Thereaction solution was added to a solution of 6.63 g of iodobenzene and0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml oftetrahydrofuran at room temperature, and the mixed solution was stirredfor 24 hours. The reaction solution was diluted with 300 ml of ethylacetate, and the dilute solution was extracted with the addition of 10%hydrochloric acid. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and then concentrated. The residuewas purified through silica-gel column chromatography (eluent: hexane)to give 6.00 g of oily 3-fluoro-4-methylbiphenyl.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.31(3H, d, J=1.8 Hz), 7.20-7.28(3H, m), 7.34(1H, m),7.43(2H, t), 7.55(2H, d)

PRODUCTION EXAMPLE 51 Production of 4-bromomethyl-3-fluorobiphenyl

A mixture of 6.00 g of 3-fluoro-4-methylbiphenyl, 5.73 g ofN-bromosuccinimide, 0.075 g of 2,2'-azobisisobutylonitrile and 120 ml ofcarbon tetrachloride was heat-refluxed for 5 hours. The reactionsolution was washed with water, and the organic layer was concentrated.The resulting residue was purified through silica-gel columnchromatography (eluent: a mixture of hexane and ethyl acetate at a ratioof 9:1) to give 8.30 g of oily 4-bromomethyl-3-fluorobiphenyl.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 4.57(2H, s), 7.30(1H, d, J=11.0 Hz), 7.34-7.40(2H,m), 7.45(3H, m), 7.56(2H, d)

PRODUCTION EXAMPLE 52 Production of ethyl3-[N-[(3-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate

In the same manner as in Production Example 14, 2.68 g of crude ethyl3-[N-[3-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate wereobtained from 1.54 g of ethyl 3-acetylamino-4-nitrobenzoate and 2.26 gof 3-fluoro-4-bromomethylbiphenyl.

EXAMPLE 247 Synthesis of6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(309)

In the same manner as in Example 24, 1.34 g of6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(309) were formed from 2.68 g of crude ethyl3-[N-[3-fluorobiphenyl-4-yl)methyl]acetylamino]-4-nitrobenzoate.

Properties of Compound (309):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.65(3H, s), 4.39(2H, q, J=7.1Hz), 5.46(2H, s), 6.79(1H, t, J=8.0 Hz), 7.25(1H, m), 7.34-7.40(2H, m),7.41-7.47(2H, m), 7.50-7.54(2H, m), 7.74(1H, d, J=8.5 Hz), 7.99(1H, dd,J=1.5 and 8.4 Hz), 8.07(1H, d, J=1.3 Hz).

EXAMPLE 248 Synthesis of6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (310)

In the same manner as in Example 53, 1.15 g of6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole (310)were formed from 1.34 g of6-ethoxycarbonyl-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole.

Properties of Compound 310:

¹ H-NMR(DMSO-d6, δ): 2.59(3H, s), 5.64(2H, s), .7.03(1H, t, J=8.0 Hz),7.37(1H, t, J=7.3 Hz), 7.42-7.48(3H, m), 7.56-7.68(4H, m), 7.79(1H, dd,J=1.4 and 8.4 Hz), 8.11(1H, s), 12.7(1H, br s).

EXAMPLE 249 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(311)

In the same manner as in Example 98, 0.236 g of6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole(311) were formed from 0.390 g of6-carboxy-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 0.351g of N,N'-carbonyldiimidazole, 0.297 g of 1-butanesulfonamide and 0.329g of diazabicycloundecene.

Properties of Compound (311):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t), 1.38(2H, m), 1.65(2H, m), 2.57(3H, s),3.48(2H, m), 5.63(2H, s), 6.93(1H, t, J=8.1 Hz), 7.37(1H, m),7.42-7.47(3H, m), 7.60(1H, dd, J=1.7 and 11.8 Hz), 7.62-7.68(3H, m),7.80(1H, dd, J=1.5 and 8.4 Hz), 8.21(1H, d, J=1.3 Hz), 11.90(1H, br s).

IR(Nujol): 1681 cm⁻¹.

mp: 227-230° C.

EXAMPLE 250 Synthesis of1-(2-chlorobenzyl)-6-[(2-methoxyethane)sulfonylcarbamoyl]-2-methylbenzimidazole(312)

In the same manner as in Example 98, 0.149 g of 1-(2-chlorobenzyl)-6-[(2-methoxyethane)sulfonylcarbamoyl ]-2-methylbenzimidazole (312) wereformed from 0.300 g of1-(biphenyl-4-ylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.258 g of (2-ethoxyethane)sulfonamide and0.256 g of diazabicycloundecene.

Properties of Compound (312):

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=6.9 Hz), 1.30(3H, t, J=8.0 Hz),2.89(2H, q, J=7.6 Hz), 3.25-3.35(2H, m), 3.63-3.74(2H, m), 5.59(2H, s),7.17(2H, d, J=8.1 Hz), 7.34(1H, t, J=7.0 Hz), 7.44(2H, t, J=7.6 Hz),7.58-7.68(5H, m), 7.82(1H, d, J=8.4 Hz), 8.23(1H, s), 11.88(1H, s).

IR(Nujol): 1681 cm⁻¹.

mp: 78-81° C.

EXAMPLE 251 Synthesis of1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(313)

In the same manner as in Example 98, 0.196 g of1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(313) were formed from 0.300 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.323 g ofN,N'-carbonyldiimidazole, 0.301 g of 1-pentanesulfonamide and 0.303 g ofdiazabicycloundecene.

Properties of Compound (313):

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.3 Hz), 1.22-1.30(2H, m),1.32-1.39(2H, m), 1.64-1.71(2H, m), 2.50(3H, s), 3.50(2H, t, J=7.8 Hz),5.59(2H, s), 6.45(1H, d, J=8.4 Hz), 7.33(1H, dd, J=2.2 and 8.5 Hz),7.69(1H, d, J=8.5 Hz), 7.76(1H, d, J=2.1 Hz), 7.80(1H, dd, J=1.6 and 8.5Hz), 8.10(1H, s), 11.89(1H, s).

IR(Nujol): 1682 cm⁻¹.

mp: 213.2-214.6° C.

EXAMPLE 252 Synthesis of1-(biphenyl-4-ylmethyl)-2-ethyl-6-[1-[3-(methylthio)propane]sulfonylcarbamoyl]benzimidazole(314)

In the same manner as in Example 98, 0.178 g of1-(biphenyl-4-ylmethyl)-2-ethyl-6-[1-[3-(methylthio)propane]sulfonylcarbamoyl]benzimidazole(314) were formed from 0.300 g of6-carboxy-1-(biphenyl-4-ylmethyl)-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.285 g of1-[(3-methylthio)propane]sulfonamide and 0.256 g ofdiazabicycloundecene.

Properties of Compound (314):

¹ H-NMR(DMSO-d6, δ): 1.30(3H, t, J=7.5 Hz), 1.91-1.99(2H, m), 1.97(3H,s), 2.58(2H, t, J=7.2 Hz), 2.90(2H, q, J=7.6 Hz), 3.55-3.61(2H, m),5.60(2H, s), 7.18(2H, d, J=8.2 Hz), 7.35(1H, t, J=7.3 Hz), 7.44(2H, t,J=7.5 Hz), 7.60-7.66(4H, m), 7.69(1H, d, J=8.5 Hz), 7.82(1H, dd, J=1.8and 8.5 Hz), 8.24(1H, s), 11.98(1H, s).

IR(Nujol): 1671 cm⁻¹.

mp: 89.9-91.2° C.

EXAMPLE 253 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(315)

In the same manner as in Example 98, 0.258 g of1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole(315) were formed from 0.300 g of6-carboxy-1-(4-biphenylmethyl)-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.254 g of 1-pentanesulfonamide and 0.256 g ofdiazabicycloundecene.

Properties of Compound (315):

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.2 Hz), 1.22-1.39(4H, m), 1.30(3H,t, J=7.5 Hz), 1.66-1.73(2H, m), 2.90(2H, q, J=7.4 Hz), 3.51(2H, t, J=7.7Hz), 5.60(2H, s), 7.18(2H, d, J=8.2 Hz), 7.34(1H, t, J=7.4 Hz), 7.44(2H,t, J=7.6 Hz), 7.60-7.67(4H, m), 7.71(1H, d, J=8.4 Hz), 7.81(1H, dd,J=1.6 and 8.4 Hz), 8.27(1H, d, J=1.1 Hz), 11.92(1H, s).

IR(Nujol): 1682 cm⁻¹.

mp: 175.3-178.4° C.

EXAMPLE 254 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dicyclobenzyl)-2-ethylbenzimidazole(316)

In the same manner as in Example 98, 0.253 g of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dicyclobenzyl)-2-ethylbenzimidazole(316) were formed from 0.300 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazole, 0.258 g ofN,N'-carbonyldiimidazole, 0.217 g of 1-butanesulfonamide and 0.262 g ofdiazabicycloundecene.

Properties of Compound (316):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.4 Hz), 1.27(3H, t, J=7.4 Hz),1.35-1.43(2H, m), 1.63-1.70(2H, m), 2.81(2H, q, J=7.4 Hz), 3.51(2H, t,J=7.7 Hz), 5.59(2H, s), 6.41(1H, d, J=8.4 Hz), 7.32(1H, dd, J=2.0 and8.4 Hz), 7.73(1H, d, J=8.4 Hz), 7.76(1H, d, J=2.0 Hz), 7.81(1H, dd,J=1.5 and 8.5 Hz), 8.12(1H, d, J=1.6 Hz), 11.87(1H, s).

IR(Nujol) 1694 cm⁻¹.

mp: 175.7-176.9° C.

EXAMPLE 255 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-[1-(3-methyl)butanesulfonylcarbamoyl]benzimidazole(317)

In the same manner as in Example 98, 0.273 g of1-(4-biphenylmethyl)-2-ethyl-6-[l-(3-methyl)butanesulfonylcarbamoyl]benzimidazole(317) were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.254 g of 1-(3-methyl)butanesulfonamide and0.256 g of diazabicycloundecene.

Properties of Compound (317):

¹ H-NMR(DMSO-d6, δ): 0.85(6H, d, J=6.5 Hz), 1.30(3H, t, J=7.4 Hz),1.55-1.62(2H, m), 1.63-1.70(1H, m), 2.90(2H, q, J=7.4 Hz), 3.52(2H, t,J=7.9 Hz), 5.61(2H, s), 7.19(2H, d, J=8.3 Hz), 7.35(1H, t, J=7.4 Hz),7.44(2H, t, J=7.5 Hz), 7.61-7.66(4H, m), 7.71(1H, d, J=8.5 Hz), 7.81(1H,dd, J=1.6 and 8.4 Hz), 8.27(1H, s), 11.95(1H,

IR(Nujol): 1682 cm⁻¹.

mp: 102.8-104.5° C.

EXAMPLE 256 Synthesis of1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole (318)

In the same manner as in Production Example 14, ethyl4-[N-(2,4-dichlorobenzyl)acetylamino]-3-nitrobenzoate was formed from1.525 g of ethyl 4-acetylamino-3-nitrobenzoate and 1.42 g of2,4-dichlorobenzyl chloride. This compound was converted into1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole [(318),1.476 g] in the same manner as in Example 24 without being purified.

Properties of Compound (318):

¹ H-NMR(CDCl₃, δ): 1.42(3H, t, J=7.1 Hz), 2.57(3H, s), 4.41(2H, q, J=7.1Hz), 5.38(2H, s), 6.35(1H, d, J=8.4 Hz), 7.09(1H, dd, J=2.0 and 8.4 Hz),7.16(1H, d, J=8.9 Hz), 7.49(1H, d, J=2.0 Hz), 7.96(1H, dd, J=1.5 and 8.5Hz), 8.46(1H, s).

EXAMPLE 257 Synthesis of5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (319)

In the same manner as in Example 53, 1.195 g of5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (319) were formedfrom 1.465 g of1-(2,4-dichlorobenzyl)-5-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (319):

¹ H-NMR(DMSO-d6, δ): 2.48(3H, s), 5.56(2H, s), 6.53(1H, d, J=8.4 Hz),7.32(1H, dd, J=2.1 and 8.4 Hz), 7.44(1H, d, J=8.4 Hz), 7.73(1H, d, J=2.2Hz), 7.78(1H, dd, J=1.5 and 8.4 Hz), 8.15(1H, d, J=1.3 Hz).

EXAMPLE 258 Synthesis of5-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(320)

In the same manner as in Example 98, 0.690 g of5-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(320) were formed from 0.565 g of5-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.504 g ofN,N'-carbonyldiimidazole, 0.427 g of 1-butanesulfonamide and 0.473 g ofdiazabicycloundecene.

Properties of Compound (320):

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.3 Hz), 1.41(2H, m), 1.68(2H, m),2.49(3H, s), 3.52(2H, m), 5.58(2H, s), 6.53(1H, d, J=8.4 Hz), 7.33(1H,dd, J=2.1 and 8.4 Hz), 7.50(1H, d, J=8.5 Hz), 7.73(1H, d, J=2.1 Hz),7.78(1H, dd, J=1.5 and 8.5 Hz), 8.24(1H, s), 11.97(1H, br s).

IR(Nujol): 1674 cm⁻¹.

mp: 135.4-139.2° C.

EXAMPLE 259 Synthesis of1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole (321)

In the same manner as in Production Example 14, ethyl4-[N-(4-biphenylmethyl)propionylamino]-3-nitrobenzoate was formed from1.50 g of 4-propionylamino-3-nitrobenzoate and 1.67 g of4-bromomethylbiphenyl. This compound was converted into1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole [(321), 1.23g] in the same manner as in Example 24 without being purified.

Properties of Compound (321):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 1.45(3H, t, J=7.6 Hz),2.90(2H, q, J=7.6 Hz), 4.39(2H, q, J=7.1 Hz), 5.40(2H, s), 7.09(2H, d,J=8.2 Hz), 7.27(1H, d, J=8.8 Hz), 7.34(1H, m), 7.42(2H, t),7.55-7.51(4H, m), 7.97(1H, dd, J=1.5 and 8.4 Hz), 8.52(1H, d, J=1.2 Hz).

EXAMPLE 260 Synthesis of1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole (322)

In the same manner as in Example 53, 0.870 g of1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole (322) were formedfrom 1.00 g of1-(4-biphenylmethyl)-5-ethoxycarbonyl-2-ethylbenzimidazole.

Properties of Compound (322):

¹ H-NMR(DMSO-d6, δ): 1.30(3H, t, J=7.4 Hz), 2.90(2H, q, J=7.4 Hz),5.57(2H, s), 7.17(2H, d, J=8.3 Hz), 7.33(1H, m), 7.42(2H, t),7.63-7.57(5H, m), 7.81(1H, dd, J=1.6 and 8.6 Hz), 8.18(1H, d, J=1.3 Hz),12.67(1H, br s).

EXAMPLE 261 Synthesis of1-(4-biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole(323)

In the same manner as in Example 98, 0.305 g of1-(4-biphenylmethyl)-5-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole(323) were formed from 0.400 g of1-(4-biphenylmethyl)-5-carboxy-2-ethylbenzimidazole, 0.364 g ofN,N'-carbonyldiimidazole, 0.308 g of 1-butanesulfonamide and 0.342 g ofdiazabicycloundecene.

Properties of Compound (323):

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.4 Hz), 1.30(3H, t, J=7.5 Hz),1.41(2H, m), 1.68(2H, m), 2.91(2H, q, J=7.4 Hz), 3.52(2H, m), 5.59(2H,s), 7.16(2H, d, J=8.2 Hz), 7.34(1H, t, J=7.4 Hz), 7.43(2H, t),7.59-7.65(5H, m), 7.80(1H, dd, J=1.6 and 8.6 Hz), 8.24(1H, d, J=1.6 Hz),11.97(1H, br s).

IR(Nujol): 1682 cm⁻¹.

mp: 142.9-144.4° C.

EXAMPLE 262 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxyethanesulfonylcarbamoyl)benzimidazole(324)

In the same manner as in Example 98, 0.487 g of1-(4-biphenylmethyl)-2-ethyl-6-(2-methoxyethanesulfonylcarbamoyl)benzimidazole(324) were formed from 0.513 g of benzimidazole, 0.464 g ofN,N'-carbonyldiimidazole, 0.420 g of 2-methoxyethanesulfonamide and0.438 g of diazabicycloundecene.

Properties of Compound (324):

¹ H-NMR(DMSO-d6, δ): 1.30(3H, t, J=7.5 Hz), 2.90(2H, q, J=7.4 Hz),3.13(3H, s), 3.70-3.77(4H, m), 5.60(2H, s). 7.18(2H, d, J=8.2 Hz),7.35(1H, t, J=7.1 Hz), 7.44(2H, t, J=7.5 Hz), 7.60-7.67(4H, m), 7.70(1H,d, J=8.5 Hz), 7.80(1H, dd, J=7.4 and 1.3 Hz), 8.25(1H, s), 11.97(1H, s).

IR(Nujol): 1684 cm⁻¹.

mp: 94.6-97.2° C.

EXAMPLE 263 Synthesis of6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole(325)

A mixture of 0.534 g of ethyl 4-propionylamino-3-aminobenzoate, 0.374 gof potassium carbonate, 0.800 g of 4-(4-fluorobenzyloxy)benzyl bromide,5 ml of ethyl acetate and 3 ml of water was stirred at 75° C. for 16hours. The organic layer was concentrated, and ethanol and 0.46 g of 36%hydrochloric acid were added to the residue. The mixture was stirred for2 hours while being heat-refluxed. The reaction mixture was neutralizedwith potassium carbonate, and the solvent was then concentrated underreduced pressure. The residue was extracted with ethyl acetate and withwater. The organic layer was concentrated under reduced pressure, andwas purified through silica-gel column chromatography (eluent: a mixtureof hexane and ethyl acetate at a ratio of 1:1) to give 0.228 g of6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole(325).

Properties of Compound (325):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 1.42(3H, t, J=7.5 Hz),2.86(2H, q, J=7.5 Hz), 4.38(2H, q, J=7.1 Hz), 4.97(2H, s), 5.32(2H, s),6.88(2H, d, J=8.7 Hz), 6.98(2H, d, J=8.7 Hz), 7.05(2H, t, J=8.7 Hz),7.37(2H, m), 7.76(2H, d, J=8.4 Hz), 7.98(1H, dd, J=1.5 and 8.5 Hz),8.02(1H, s).

EXAMPLE 264 Synthesis of6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (326)

In the same manner as in Example 53, 0.175 g of6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (326)were formed from 0.225 g of6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole.

Properties of Compound (326):

¹ H-NMR(DMSO-d6, δ): 1.28(3H, t, J=7.4 Hz), 2.89(2H, q, J=7.4 Hz),5.01(2H, s), 5.47(2H, S), 6.95(2H, d), 7.03(2H, d), 7.18(2H, t),7.45(2H, m), 7.62(1H, d, J=8.4 Hz), 7.77(1H, d, J=8.4 Hz), 8.05(1H, s).

EXAMPLE 265 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazoleammonium salt (327)

In the same manner as in Example 98, oily6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazolewas obtained from 0.171 g of6-carboxy-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole, 0.137 gof N,N'-carbonyldiimidazole, 0.116 g of butanesulfonamide and 0.129 g ofdiazabicycloundecene. This compound was dissolved in ethyl acetate, andaqueous ammonia was added thereto. The solid material precipitated wasseparated through filtration, and was dried to give 0.140 g of6-(1-butanesulfonylcarbamoyl)-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazoleammonium salt (327).

Properties of Compound (327):

¹ H-NMR(DMSO-d6, δ): 0.83(3H, t), 1.25(3H, t), 1.35(2H, m),1.61(2H, m),2.84(2H, q), 3.27(2H, m), 5.01(2H, s), 5.42(2H, s), 6.95(2H, d, J=7.8Hz), 7.02(2H, d, J=7.8 Hz), 7.17(2H, t), 7.44(2H, m), 7.57(1H, d, J=8.1Hz), 7.82(1H, d, J=8.1 Hz), 8.12(1H, s).

IR(Nujol): 1614 cm⁻¹.

mp: 105-115° C.

EXAMPLE 266 Synthesis of1-[4-(3,4-dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole(328)

In the same manner as in Example 263, 2.01 g of1-[4-(3,4-dichlorobenzyloxy)benzyl]-6-ethoxycarbonyl-2-ethylbenzimidazole(328) were formed from 1.81 g of ethyl 4-propionylamino-3-aminobenzoateand 3.18 g of 4-(3,4-dichlorobenzyloxy)benzyl bromide.

Properties of Compound (328):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 1.42(3H, t, J=7.5 Hz),2.86(2H, q, J=7.5 Hz), 4.38(2H, q, J=7.1 Hz), 4.97(2H, s), 5.33(2H, s),6.87(2H, m), 6.98(2H, m), 7.22(1H, dd, J=2.0 and 8.3 Hz), 7.44(1H, d,J=8.3 Hz), 7.50(1H, d, J=2.0 Hz), 7.76(1H, d, J=8.6 Hz), 7.97(1H, dd,J=1.6 and 8.6 Hz), 8.02(1H, d, J=1.3 Hz).

EXAMPLE 267 Synthesis of6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole (329)

In the same manner as in Example 53, 1.82 g of6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole (329)were formed from 2.01 g of6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole.

Properties of Compound (329):

¹ H-NMR(DMSO-d6, δ): 1.28(3H, t), 2.88(2H, q), 5.05(2H, s), 5.47(2H, s),6.96(2H, d), 7.04(2H, d), 7.39(1H, m), 7.68-7.59(3H, m), 7.78(1H, d,J=8.4 Hz), 8.06(1H, s).

EXAMPLE 268 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazoleammonium salt (330)

Oily6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazolewas obtained from 0.500 g of6-carboxy-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazole,0.356 g of N,N'-carbonyldiimidazole, 0.301 g of butanesulfonamide and0.334 g of diazabicycloundecene in the same manner as in Example 98.This compound was dissolved in ethyl acetate, and aqueous ammonia wasadded thereto. The solid material precipitated was separated throughfiltration, and was dried to give 0.51 g of6-(1-butanesulfonylcarbamoyl)-1-[4-(3,4-dichlorobenzyloxy)benzyl]-2-ethylbenzimidazoleammonium salt (330).

Properties of Compound (330)

¹ H-NMR(DMSO-d6, δ): 0.82(3H, t, J=7.3 Hz), 1.26(3H, t, J=7.4 Hz),1.31(2H, m), 1.54(2H, m), 2.84(2H, q, J=7.4 Hz), 3.07(2H, m), 5.05(2H,s), 5.41(2H, s), 6.95(2H, d, J=8.7 Hz), 7.00(2H, d, J=8.7 Hz), 7.41(1H,d, J=8.2 Hz), 7.46(1H, d, J=8.4 Hz), 7.62(1H, d, J=8.2 Hz), 7.68(1H, s),7.81(1H, d, J=8.4 Hz), 7.97(1H, s).

IR(Nujol): 1540 cm⁻¹.

mp: 99.5-101.5° C.

EXAMPLE 269 Synthesis of1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethylbenzimidazole (331)

In the same manner as in Example 15, 0.295 g of1-(4-biphenylmethyl)-6-(n-butylcarbamoyl)-2-ethylbenzimidazole (331)were formed from 0.400 g of1-(4-biphenylmethyl)-6-chlorocarbonyl-2-ethylbenzimidazolehydrochloride, 0.233 g of n-butylamine and 0.215 g of triethylamine.

Properties of Compound (331):

¹ H-NMR(DMSO-d6, δ): 0.95(3H, t, J=7.3 Hz), 1.37-1.48(2H, m), 1.45(3H,t, J=7.4 Hz), 1.57-1.63(2H, m), 2.90(2H, q, J=7.5 Hz), 3.46(2H, q, J=7.1Hz), 5.42(2H, s), 6.16(1H, br s), 7.10(2H, d, J=8.1 Hz), 7.34(1H, t,J=7.5 Hz), 7.42(2H, t, J=7.5 Hz), 7.48-7.57(5H, m), 7.87(1H, d, J=8.4Hz), 7.91(1H, s).

IR(Nujol): 1621 cm⁻¹.

mp: 170.5-173.0° C.

EXAMPLE 270 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-ylcarbamoyl)benzimidazole(332)

In the same manner as in Example 15, 0.179 g of1-(4-biphenylmethyl)-2-ethyl-6-(thiazol-2-ylcarbamoyl)benzimidazole(332) were obtained from 0.400 g of1-(4-biphenylmethyl)-6-chlorocarbonyl-2-ethylbenzimidazolehydrochloride, 0.318 g of 2-aminothiazole and 0.215 g of triethylamine.

Properties of Compound (332):

¹ H-NMR(DMSO-d6, δ): 1.48(3H, t, J=7.5 Hz), 2.95(2H, q, J=7.5 Hz),5.41(2H, s), 6.94(1H, d, J=3.6 Hz), 7.06(2H, d, J=8.1 Hz), 7.26(1H, d,J=3.6 Hz), 7.32(1H, t, J=7.4 Hz), 7.39(2H, t, J=7.3 Hz), 7.47-7.51(4H,m), 7.87(2H, s), 8.03(1H, s), 11.15(1H, s).

IR(Nujol): 1652 cm⁻¹.

mp: 225.5-227.7° C.

EXAMPLE 271 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(2-pyridylcarbamoyl)benzimidazole (333)

In the same manner as in Example 98, 0.116 g of1-(4-biphenylmethyl)-2-ethyl-6-(2-pyridylcarbamoyl)benzimidazole (333)were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.158 g of 2-aminopyridine and 0.256 g ofdiazabicycloundecene.

Properties of Compound (333):

¹ H-NMR(CDCl₃, δ): 1.47(3H, t, J=7.6 Hz), 2.93(2H, q, J=7.4 Hz),5.45(2H, s), 7.06(1H, dd, J=7.4 and 4.9 Hz), 7.10(2H, d, J=8.1 Hz),7.34(1H, t, J=7.4 Hz), 7.42(2H, t, J=7.6 Hz), 7.50-7.55(4H, m), 7.75(1H,t, J=7.9 Hz), 7.79(1H, d, J=8.4 Hz), 7.86(1H, d, J=8.4 Hz), 7.98(1H, s),8.30(1H, d, J=6.2 Hz), 8.38(1H, d, J=8.4 Hz), 8.62(1H,s).

IR(Nujol): 1661 cm⁻¹.

mp: 160.9-164.5° C.

EXAMPLE 272 Synthesis of6-(n-butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole (334)

In the same manner as in Example 15, 0.156 g of6-(n-butylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (334)were formed from 0.300 g of6-chlorocarbonyl-1-(2,4-dichlorobenzyl)-2-ethylbenzimidazolehydrochloride, 0.181 g of triethylamine and 0.196 g of n-butylamine.

Properties of Compound (334):

¹ H-NMR(CDCl₃, δ): 0.96(3H, t, J=7.3 Hz), 1.37-1.43(2H, m),1.55-1.62(2H, m), 2.56(3H, s), 3.46(2H, q, J=7.0 Hz), 5.40(2H, s),6.15(1H, br s), 6.32(1H, d, J=8.5 Hz), 7.07(1H, d, J=8.4 Hz), 7.48(1H,d, J=2.0 Hz), 7.55(1H, d, J=8.4 Hz), 7.74(1H, d, J=8.4 Hz), 7.79(1H,s).

IR(Nujol): 1636 cm⁻¹.

mp: 146.6-147.5° C.

PRODUCTION EXAMPLE 53 Production of ethyl3-[sec-(2,4-dichlorophenetyl)amino]-4-nitrobenzoate

A solution of 0.877 g of 3-fluoro-4-nitrobenzoic acid and 2.25 g ofsec-(2,4-dichlorophenetyl)amine in 5 ml of toluene was heat-refluxed for15 hours. After the solvent was distilled off, the residue was purifiedthrough silica-gel column chromatography to obtain crude3-[sec-(2,4-dichlorophenetyl)amino]-4-nitrobenzoic acid. To thiscompound were added 80 ml of ethanol and 3.0 g of 97% sulfuric acid, andthe mixture was heat-refluxed for 4.5 hours. After ethanol was distilledoff under reduced pressure, the residue was extracted with chloroformand with a saturated aqueous solution of sodium hydrogencarbonate. Theorganic layer was dried, and was then concentrated under reducedpressure. The residue was purified through silica-gel columnchromatography (eluent: a mixture of hexane and ethyl acetate at a ratioof 2:1) to give 1.16 g of ethyl3-[sec-(2,4-dichlorophenetyl)amino]-4-nitrobenzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.35(3H, t, J=7.1 Hz), 1.64(3H, d, J=6.6 Hz),4.30(2H, q, J=7.1 Hz), 5.16(1H, m), 7.18-7.31(4H, m), 7.43(1H, d, J=2.0Hz), 8.21(1H, d, J=8.8 Hz), 8.34(1H, d, J=5 Hz).

PRODUCTION EXAMPLE 54 Production of ethyl4-amino-3-[sec-(2,4-dichlorophenetyl)amino]benzoate

A mixture of 1.14 g of ethyl3-[sec-(2,4-dichlorophenetyl)amino]-4-nitrobenzoate, 1.60 g of reducediron, 10 ml of ethanol and 5 ml of acetic acid was heat-refluxed for 3hours. The solid material was separated through filtration, and thefiltrate was concentrated. The residue was extracted with chloroform andwith 10% hydrochloric acid. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate, and the solventwas distilled off under reduced pressure. The residue was purifiedthrough silica-gel column chromatography (eluent: a mixture of hexaneand ethyl acetate at a ratio of 2:1) to give 0.920 g of ethyl4-amino-3-[sec-(2,4-dichlorophenetyl)amino]benzoate.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 1.31(3H, t, J=7.1 Hz), 1.52(3H, d, J=6.7 Hz),3.56(1H, br s), 3.79(2H, br s), 4.23(2H, q, J=7.1 Hz), 4.96(1H, q, J=6.7Hz), 6.68(1H, d, J=8.0 Hz), 7.03(1H, d, J=1.7 Hz), 7.15(1H, dd, J=2.1and 8.4 Hz), 7.35(1H, d, J=8.4 Hz), 7.39-7.43(2H, m).

EXAMPLE 273 Synthesis of1-[sec-(2,4-dichlorophenetyl)]-6-ethoxycarbonyl-2-methylbenzimidazole(335)

Acetyl chloride (0.243 g) was added dropwise to a solution of 0.900 g ofethyl 4-amino-3-[sec-2,4-dichlophenetyl)amino]benzoate in 2.0 ml ofpyridine at room temperature. Further, the mixture was stirred at roomtemperature for 1 hour, and the reaction mixture was then extracted withthe addition of ethyl acetate and excess 10% hydrochloric acid. Theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate, and the solvent was distilled off under reducedpressure to obtain crude ethyl4-4-acetylamino-3-[sec-(2,4-dichlorophenetyl)amino]benzoate. This crudeproduct was immediately dissolved in 20 ml of ethanol, and 0.4 ml of 36%hydrochloric acid were added to the solution. The mixture washeat-refluxed for 2 hours. The reaction solution was neutralized withsodium hydrogencarbonate, and the solvent was distilled off underreduced pressure. The residue was extracted with ethyl acetate and withwater. The organic layer was concentrated, and the residue was purifiedthrough silica-gel column chromatography (eluent: a mixture of ethylacetate and methanol at a ratio of 20:1) to give 0.700 g of1-[sec-(2,4-dichlorophenetyl)]-6-ethoxycarbonyl-2-methylbenzimidazole(335).

Properties of Compound (335):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.2 Hz), 2.01(3H, d, J=7.2 Hz),2.63(3H, s), 4.29-4.40(2H, m), 5.89(1H, q, J=7.2 Hz), 7.37(1H, dd, J=2.2and 8.4 Hz), 7.40(1H, d, J=2.0 Hz), 7.52(1H, d, J=8.4 Hz), 7.67(1H, d,J=8.4 Hz), 7.86(1H, s), 7.91(1H, dd, J=1.4 and 8.4 Hz).

EXAMPLE 274 Synthesis of6-carboxy-1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole (336)

In the same manner as in Example 53, 0.447 g of6-carboxy-1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole (336)were formed from 0.690 g of1-[sec-(2,4-dichlorophenetyl)]-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (336):

¹ H-NMR(DMSO-d6, δ): 1.88(3H, d, J=6.8 Hz), 2.57(3H, s), 6.01(1H, q),7.55(1H, d), 7.60-7.67(3H, m), 7.71(1H, d), 7.89(1H, d), 12.65(1H, brs).

EXAMPLE 275 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole(337)

In the same manner as in Example 98,6-(1-butanesulfonylcarbamoyl)-1-[sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole(336) was formed from 0.433 g of6-carboxy-1-(sec-(2,4-dichlorophenetyl)]-2-methylbenzimidazole, 0.412 gof N,N'-carbonyldiimidazole, 0.348 g of butanesulfonamide and 0.386 g ofdiazabicycloundecene.

Properties of Compound (337)

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.3 Hz), 1.34(2H, m), 1.57(2H, m),1.89(3H, d, J=7.0 Hz), 2.49(3H, s), 3.07(2H, m), 5.954(1H, q, J=7.0 Hz),7.41(1H, d, J=8.7 Hz), 7.56(1H, dd, J=2.1 and 8.5 Hz), 7.61(1H, d, J=2.1Hz), 7.74-7.79(3H, m).

EXAMPLE 276 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)benzimidazole (338)

In the same manner as in Example 15, 0.195 g of1-(4-biphenylmethyl)-2-ethyl-6-(phenylcarbamoyl)benzimidazole (338) wereformed from 0.300 g of1-(4-biphenylmethyl)-6-chlorocarbonyl-2-ethylbenzimidazolehydrochloride, 0.243 g of triethylamine and 0.224 g of aniline.

Properties of Compound (338):

¹ H-NMR(CDCl₃, δ): 1.47(3H, t, J=7.5 Hz), 2.93(2H, q, J=7.5 Hz),5.44(2H, s), 7.11(2H, d, J=8.2 Hz), 7.14(1H, t, J=7.4 Hz), 7.32-7.38(3H,m), 7.42(2H, t, J=7.4 Hz), 7.51-7.54(4H, m), 7.63(2H, d, J=7.8 Hz),7.69(1H, dd, J=8.4 and 1.6 Hz), 7.84(1H, d, J=8.4 Hz), 7.88(1H, br s),7.97(1H,d,J=1.5 Hz).

IR(Nujol): 1647 cm⁻¹.

mp: 171.7-172.1° C.

EXAMPLE 277 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)benzimidazole(339)

In the same manner as in Example 98, 0.234 g of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-thiadiazol-2-ylcarbamoyl)benzimidazole(339) were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.170 g of 2-amino-1,3,4-thiadiazole and 0.256g of diazabicycloundecene.

Properties of Compound (339):

¹ H-NMR(CDCl₃,δ): 1.45(3H, t, J=7.5 Hz), 2.90(2H, q, J=7.5 Hz),5.53(2H,s), 7.07(2H, d, J=8.3 Hz), 7.33(1H, t, J=7.5 Hz), 7.40(2H, t,J=7.3 Hz), 7.52(4H, d, J=8.2 Hz), 7.89(1H, d, J=8.5 Hz), 8.08(1H, dd,J=8.5 and 1.6 Hz), 8.34(1H, d, J=1.2 Hz), 7.60(1H, s), 12.26(1H, s).

IR(Nujol): 1654 cm⁻¹.

mp: 230.1-233.4° C.

EXAMPLE 278 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole(340)

In the same manner as in Example 98, 0.135 g of1-(4-biphenylmethyl)-2-ethyl-6-(tetrazol-5-ylcarbamoyl)benzimidazole(340) were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.143 g of 5-aminotetrazole and 0.256 g ofdiazabicycloundecene.

Properties of Compound (340)

¹ H-NMR(DMSO-d6,δ): 1.32(3H, t, J=7.5 Hz), 2.93(2H, q, J=7.5 Hz),5.61(2H, s), 7.23(2H, d, J=8.1 Hz), 7.34(1H, t, J=7.4 Hz), 7.44(2H, t,J=7.6 Hz), 7.60-7.67(4H, m), 7.76(1H, d, J=8.5 Hz), 7.98(1H, d, J=8.6Hz), 8.46(1H, s), 12.30(1H, s), 15.95(1H, s).

IR(Nujol): 1667 cm⁻¹.

mp: 273.1-276.0° C.

EXAMPLE 279 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-ylcarbamoyl)benzimidazole(341)

In the same manner as in Example 98, 0.224 g of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-3-ylcarbamoyl)benzimidazole(341) were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.141 g of 3-amino-1,3,4-triazole and 0.256 gof diazabicycloundecene.

Properties of Compound (341):

¹ H-NMR(DMSO-d6,δ): 1.33(3H, t, J=7.4Hz), 2.93(2H, q, J=7.4 Hz),5.63(2H, s), 7.17(2H, d, J=8.3 Hz), 7.35(1H, t, J=7.4 Hz), 7.44(2H, t,J=7.5 Hz), 7.60-7.65(4H, m), 7.78(1H, d, J=7.4 Hz), 7.83(1H, dd, J=8.4and 1.5 Hz), 8.17(1H, s), 8.77(2H, s), 12.04(1H, s).

IR(Nujol): 1675 cm⁻¹.

mp: 263.4-266.2° C.

EXAMPLE 280 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-2-ylcarbamoyl)benzimidazole(342)

In the same manner as in Example 98, 0.215 g of1-(4-biphenylmethyl)-2-ethyl-6-(1,3,4-triazol-2-ylcarbamoyl)benzimidazole(342) were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.141 g of 2-amino-1,3,4-triazole and 0.256 gof diazabicycloundecene.

Properties of Compound (342):

¹ H-NMR(DMSO-d6, δ): 1.31(3H, t, J=7.4 Hz), 2.92(2H, q, J=7.4 Hz),5.60(2H, s), 7.23(2H, d, J=7.8 Hz), 7.34(1H, t, J=7.2 Hz), 7.44(2H, t,J=7.6 Hz), 7.60-7.66(4H, m), 7.72(1H, d, J=8.3 Hz), 7.78(1H, s),7.95(1H, d, J=8.3 Hz), 8.43(1H, s), 11.85(1H, s), 13.57(1H, s).

IR(Nujol): 1659 cm⁻¹.

mp: 306.0° C.(decomp.).

EXAMPLE 281 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(3-pyridylcarbamoyl)benzimidazole (343)

In the same manner as in Example 98, 0.229 g of1-(4-biphenylmethyl)-2-ethyl-6-(3-pyridylcarbamoyl)benzimidazole (343)were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.158 g of 3-aminopyridine and 0.256 g ofdiazabicycloundecene.

Properties of Compound (343):

¹ H-NMR(CDCl₃, δ): 1.47(3H, t, J=7.6 Hz), 2.93(2H, q, J=7.4 Hz),5.45(2H, s), 7.10(2H, d, J=8.1 Hz), 7.29-7.36(2H, m), 7.42(2H, t, J=7.4Hz), 7.53(4H, d, J=8.0 Hz), 7.71(1H, d, J=8.5 Hz), 7.86(1H, d, J=8.4Hz), 7.97(1H, s), 7.98(1H, s), 8.27(1H, d, J=8.4 Hz), 8.38(1H, d, J=4.7Hz), 8.68(1H, d, J=2.5 Hz).

IR(Nujol): 1644 cm⁻¹.

mp: 124.4-125.6° C.

EXAMPLE 282 Synthesis of1-(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)benzimidazole(344)

In the same manner as in Example 98, 0.152 g of1-(2,4-dichlorobenzyl)-2-methyl-6-(2-pyridylcarbamoyl)benzimidazole(344) were formed from 0.300 g of6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 0.290 g ofN,N'-carbonyldiimidazole, 0.168 g of 2-aminopyridine and 0.273 g ofdiazabicycloundecene.

Properties of Compound (344):

¹ H-NMR(CDCl₃, δ): 2.59(3H, s), 5.43(2H, s), 6.33(1H, d, J=8.4 Hz),7.06-7.10(2H, m), 7.50(1H, d, J=2.1 Hz), 7.77(1H, dt, J=7.8 and 1.9 Hz),7.83(2H, s), 7.88(1H, s), 8.30(1H, d, J=3.7 Hz), 8.39(1H, d, J=8.3 Hz),8.78(1H, s).

IR(Nujol): 1666 cm⁻¹.

mp: 157.4-159.2° C.

EXAMPLE 283 Synthesis of1-(4-biphenylmethyl)-2-ethyl-6-(4-pyridylcarbamoyl)benzimidazole (345)

In the same manner as in Example 98, 0.153 g of1-(4-biphenylmethyl)-2-ethyl-6-(4-pyridylcarbamoyl)benzimidazole (345)were formed from 0.300 g of1-(4-biphenylmethyl)-6-carboxy-2-ethylbenzimidazole, 0.272 g ofN,N'-carbonyldiimidazole, 0.158 g of 4-aminopyridine and 0.256 g ofdiazabicycloundecene.

Properties of Compound (345):

¹ H-NMR(CDCl₃, δ): 1.48(3H, t, J=7.4 Hz), 2.94(2H, q, J=7.4 Hz),5.45(2H, s), 7.10(2H, d, J=8.1 Hz), 7.35(1H, t, J=7.4 Hz), 7.42(2H, t,J=7.4 Hz), 7.50-7.60(6H, m), 7.691(1H, d, J=7.8 Hz), 7.86(1H, d, J=8.3Hz), 7.95(1H, s), 7.99(1H, br s), 8.54(2H, dd, J=1.5 and 4.7 Hz).

IR(Nujol): 1663 cm⁻¹.

mp: 123.8-124.7° C.

PRODUCTION EXAMPLE 55 Production ofN-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide

In the same manner as in Production Example 28, 10.75 g ofN-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide were formed from10.0 g of 4-acetylamino-3-nitrobenzoic acid, 9.40 g ofN,N'-carbonyldiimidazole, 7.92 g of 1-butanesulfonamide and 8.83 g ofdiazabicycloundecene.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.4 Hz), 1.37-1.44(2H, m),1.64-1.71(2H, m), 2.12(3H, s), 3.52(2H, t, J=7.7 Hz), 7.83(1H, d, J=8.6Hz), 8.21(1H, dd, J=8.6 and 2.1 Hz), 8.54(1H, d, J=2.2 Hz), 10.56(1H,s), 12.32(1H, s).

PRODUCTION EXAMPLE 56 Production ofN-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide

In the same manner as in Production Example 29, 3.04 g ofN-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide were formed from10.75 g of N-(1-butanesulfonyl)-4-acetylamino-3-nitrobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.3 Hz), 1.33-1.43(2H, m),1.59-1.67(2H, m), 2.07(3H, s), 3.37-3.43(2H, t), 5.12(2H, br s),7.13(1H, dd, J=8.2 and 2.0 Hz), 7.28(1H, d, J=1.9 Hz), 7.40(1H, d, J=8.3Hz), 9.09(1H, s).

PRODUCTION EXAMPLE 57 Production ofN-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]benzamide

In the same manner as in Production Example 32, crudeN-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]benzamidewas obtained from 0.400 g ofN-(1-butanesulfonyl)-3-amino-4-acetylaminobenzamide and 0.477 g of2-[(4-bromomethyl)phenyl]pyridine. This product was used in thesubsequent reaction at once.

EXAMPLE 284 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methylbenzimidazole(346)

In the same manner as in Example 183, 0.330 g of6-(1-butanesulfonylcarbamoyl)-1-[4-(2-pyridyl)benzyl]-2-methylbenzimidazole(346) were obtained from the above-mentioned crudeN-(1-butanesulfonyl)-4-acetylamino-3-[4-(2-pyridyl)benzylamino]benzamide.

Properties of Compound (346):

¹ H-NMR(DMSO-d6, δ): 0.82(3H, t), 1.37-1.46(2H, m), 1.54-1.61(2H, m),2.54(3H, s), 3.10(2H, t, J=7.8 Hz), 5.57(2H, s), 7.19(2H, d, J=7.5 Hz),7.33(1H, t, J=5.2 Hz), 7.49(1H, d, J=8.4 Hz), 7.82-7.87(2H, m), 7.90(1H,d, J=8.0 Hz), 8.01-8.04(3H, m), 8.63(1H, d, J=4.2 Hz).

IR(Nujol): 1722 cm⁻¹.

mp: 292.4-298.4° C.

EXAMPLE 285 Synthesis of5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (347) and6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (348)

Four grams of 1-(2,4-dichlorobenzyl)-2-methylbenzimidazole were added to20 ml of chlorosulfonic acid in an ice bath, and the mixture was stirredat room temperature for 24 hours and then at 80° C. for 1.5 hours. Thereaction solution was poured into ice water, and the gum solid materialprecipitated was separated through filtration to obtain a mixture of5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (347) and6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (348).This mixture was used in the subsequent reaction at once.

EXAMPLE 286 Synthesis of5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (349) and6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (350)

The mixture of5-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and6-chlorosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole obtainedin Example 285 was immediately treated with 100 ml of 25% aqueousammonia at room temperature for 1 hour. The solid material was separatedthrough filtration to give 2.68 g of a mixture of5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (349) and6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (350) at aratio of 1:1.

Properties of the mixture of Compound (349) and Compound (350):

¹ H-NMR(CD3OD, δ): 2.52(3/2H, s), 2.54(3/2H, s), 5.54(2H, s), 6.55(1H,d, J=6.9 Hz), 7.17(1H, d, J=8.0 Hz), 7.52(1H, s), 7.65-7.78(2H, m),7.82(1/2H, s), 8.11(1/2H, s).

EXAMPLE 287 Synthesis of6-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(351) and5-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(352)

One milliliter of chloroform, 0.56 ml of triethylamine and 0.326 g ofn-valeryl chloride were added to 0.500 g of a mixture of5-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole and6-aminosulfonyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole at a ratioof 1:1, and the mixture was stirred at room temperature for 48 hours.Water was added thereto to stop the reaction, and the reaction solutionwas extracted with chloroform. The organic layer was dried,concentrated, and purified through silica-gel column chromatography(eluent: a mixture of chloroform and methanol at a ratio of 95:5) toobtain 0.360 g of a mixture of5-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazoleand6-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole.Further, this mixture was purified through medium-pressure silica-gelcolumn chromatography (eluent: a mixture of hexane and ethyl acetate ata ratio of from 1:1 to 1:4) to give 0.95 g of6-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(351) and 0.45 g of5-(n-valerylaminosulfonyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(352).

Properties of Compound (351):

¹ H-NMR(DMSO-d6, δ): 0.74(3H, t, J=7.3 Hz), 1.09(2H, m), 1.31(2H, m),2.10(2H, t, J=7.3 Hz), 2.53(3H, s), 5.63(2H, s), 6.60(1H, d, J=8.4 Hz),7.32(1H, d, J=8.3 Hz), 7.67-7.77(3H, m), 7.93(1H, s).

IR(KBr): 1726 cm⁻¹.

mp: 207.5-210.0° C.

Mass(FD): m/e 454(M+1).

Properties of Compound (352):

¹ H-NMR(DMSO-d6, δ): 0.75(3H, t, J=7.3 Hz), 1.11(2H, m), 1.34(2H, m),2.13(2H, t, J=7.4 Hz), 2.51(3H, s), 5.59(2H, s), 6.57(1H, d, J=8.5 Hz),7.32(1H, dd, J=2.2 and 8.4 Hz), 7.57(1H, d, J=8.6 Hz), 7.67(1H, dd,J=1.6 and 8.6 Hz), 7.73(1H, d, J=2.1 Hz), 8.08(1H, d, J=1.6 Hz).

IR(KBr): 1706 cm⁻¹.

mp: 213.0-216.0° C.

EXAMPLE 288 Synthesis of 2,4-dimethyl-6-methoxycarbonylbenzimidazole

Methyl 4-acetylamino-5-amino-3-methylbenzoate was obtained from methyl4-amino-3-methylbenzoate by the method described in Journal of MedicinalChemistry, 1993, 36, 4040-4051. Subsequently, this compound washeat-refluxed in acetic acid for 2 hours to give2,4-dimethyl-6-methoxycarbonylbenzimidazole.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 2.55(3H, s), 2.62(3H, s), 3.91(3H, s), 7.74(1H, s),8.07(1H, s), 10.65(1H, br s).

EXAMPLE 289 Synthesis of1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole (353)

A mixture containing 0.900 g of2,4-dimethyl-6-methoxycarbonylbenzimidazole, 1.20 g of2,4-dichlorobenzyl chloride, 0.200 g of sodium iodide, 0.610 g ofpotassium carbonate and 4 ml of N,N-dimethylformamide was stirred at 80°C. for 16 hours. After the organic solvent was distilled off underreduced pressure, the residue was extracted with ethyl acetate and withwater. The organic layer was concentrated, and was crystallized with theaddition of hexane. The crystals were separated through filtration, andwere dried to give 1.08 g of1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole(353).

Properties of Compound (353):

¹ H-NMR(CDCl₃, δ): 2.58(3H, s), 2.71(3H, s), 3.90(3H, s), 5.39(2H, s),6.30(1H, d, J=8.4 Hz), 7.07(1H, dd, J=8.4 and 2.0 Hz), 7.49(1H, d, J=2.0Hz), 7.75(1H, s), 7.81(1H,s).

EXAMPLE 290 Synthesis of6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole (354)

In the same manner as in Example 53, 0.435 g of6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole (354) wereformed from 0.510 g of1-(2,4-dichlorobenzyl)-2,4-dimethyl-6-methoxycarbonylbenzimidazole.

Properties of Compound (354):

¹ H-NMR(DMSO-d6, δ): 2.51(3H, s), 2.55(3H, s), 5.57(2H, s), 6.49(1H, d,J=8.4 Hz), 7.31(1H, dd, J=8.4 and 2.2 Hz), 7.62(1H, s), 7.72(1H, d,J=2.0 Hz), 7.78(1H, s), 12.64(1H, br s).

EXAMPLE 291 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole(355)

In the same manner as in Example 98, 0.468 g of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole(355) were formed from 0.417 g of6-carboxy-1-(2,4-dichlorobenzyl)-2,4-dimethylbenzimidazole, 0.290 g ofN,N'-carbonyldiimidazole, 0.246 g of 1-butenesulfonamide and 0.273 g ofdiazabicycloundecene.

Properties of Compound (355):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.4 Hz), 1.38(2H, m), 1.64(2H, m),2.49(3H, s), 2.56(3H, s), 3.48(2H, t), 5.55(2H, s), 6.40(1H, d, J=8.5Hz), 7.31(1H, dd, J=2.1 and 8.4 Hz), 7.64(1H, s), 7.75(1H, d, J=2.1 Hz),7.90(1H, s), 11.79(1H, br s).

IR(Nujol): 1682 cm⁻¹.

mp: 180.0-181.5° C.

PRODUCTION EXAMPLE 58 Production of 4-phenoxybenzyl alcohol

Sodium borohydride (0.48 g) was added to a solution of 4.96 g of4-phenoxybenzaldehyde in 20 ml of ethanol, and the mixture was stirredat room temperature for 1.5 hours. After the completion of theconcentration, the residue was extracted with tert-butylmethyl ether andwith water. The organic layer was concentrated to give 4.84 g of4-phenoxybenzyl alcohol.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 4.67(2H, d, J=5.7 Hz), 6.99-7.01(4H, m), 7.10(1H, t,J=7.4 Hz), 7.32-7.35(4H, m).

PRODUCTION EXAMPLE 59 Production of 4-phenoxybenzyl chloride

Thionyl chloride (13.34 g) was added to 4.06 g of 4-phenoxybenzylalcohol, and the mixture was stirred at 80° C. for 3.5 hours. After thecompletion of the concentration, the reaction mixture was extracted withethyl acetate and with water. The organic layer was concentrated to give4.31 g of 4-phenoxybenzyl chloride.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 4.58(2H, s), 6.96-7.03(4H, m), 7.11-7.14(1H, m),7.32-7.37(4H, m).

EXAMPLE 292 Synthesis of6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)benzimidazole (356)

In the same manner as in Example 263, 0.49 g of ethyl4-acetylamino-3-[(4-phenoxy)benzylamino]benzoate were obtained from 0.56g of ethyl 4-acetylamino-3-aminobenzoate, 0.33 g of sodium carbonate,0.12 g of sodium iodide and 0.66 g of 4-phenoxybenzyl chloride.Subsequently, this compound was converted into6-ethoxycarbonyl-2-methyl-1-(4-phenoxybenzyl)benzimidazole [(356), 0.44g].

Properties of ethyl 4-acetylamino-3-[(4-phenoxy)benzylamino]benzoate:

¹ H-NMR(CDCl₃, δ): 1.37(3H, t, J=7.1 Hz), 2.04(3H, s), 4.18(1H, br s),4.31-4.36(4H, m), 6.98-7.02(4H, m), 7.09-7.12(1H, m), 7.27-7.51(8H, m).

Properties of Compound (356):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.61(3H, s), 4.39(2H, q, J=7.1Hz), 5.35(2H, s), 6.92-6.95(2H, m), 6.97-7.00(2H, m), 7.02(2H, d, J=8.7Hz), 7.09-7.13(1H, m), 7.31-7.34(2H, m), 7.72(1H, d, J=8.6 Hz), 7.98(1H,dd, J=1.5 and 8.4 Hz), 8.04(1H, d, J=1.2 Hz).

EXAMPLE 293 Synthesis of6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole (357)

In the same manner as in Example 53, 0.37 g of6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole (357) were formedfrom 0.44 g of6-ethoxycarbonyl-2-methyl-1-(4-phenoxy)benzylbenzimidazole.

Properties of Compound (357):

¹ H-NMR(DMSO-d6, δ): 2.57(3H, s), 5.54(2H, s), 6.95-6.97(4H, m),7.09-7.13(3H, m), 7.33-7.37(2H, m), 7.60(1H, d, J=8.4 Hz), 7.78(1H, d,J=8.4 Hz), 8.07(1H, s), 12.72(1H, br s).

EXAMPLE 294 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(4-phenoxybenzyl)benzimidazole(358)

In the same manner as in Example 98, 0.19 g of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(4-phenoxybenzyl)benzimidazole(358) were obtained from 0.36 g of6-carboxy-2-methyl-1-(4-phenoxybenzyl)benzimidazole, 0.24 g ofN,N'-carbonyldiimidazole, 0.21 g of 1-butanesulfonamide and 0.23 g ofdiazabicycloundecene.

Properties of Compound (358):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.4 Hz), 1.40(2H, m), 1.68(2H, m),2.54(3H, s), 3.52(2H, t, J=7.8 Hz), 5.51(2H, s), 6.96-6.98(4H, m),7.11(1H, t, J=7.4 Hz), 7.17(2H, d, J=8.6 Hz), 7.34-7.37(2H, m), 7.64(1H,d, J=8.5 Hz), 7.79(1H, dd, J=1.5 and 8.5 Hz), 8.24(1H, s), 11.92(1H, brs).

IR(Nujol): 1632 cm⁻¹.

mp: 183.4-184.4° C.

EXAMPLE 295 Synthesis of6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole (359)

In the same manner as in Example 263, 0.656 g of6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole (359) wereformed from 0.600 g of ethyl 4-acetylamino-3-aminobenzoate, 0.450 g ofpotassium carbonate, 0.122 g of sodium iodide and 0.413 g of2-chloromethylpyridine. This compound was used in the subsequentreaction at once.

EXAMPLE 296 Synthesis of6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole (360)

In the same manner as in Example 53, 0.532 g of6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole (360) were formedfrom 0.656 g of6-ethoxycarbonyl-2-methyl-1-(2-pyridylmethyl)benzimidazole.

Properties of Compound (360):

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 5.56(2H, s), 7.22(1H, d, J=7.9 Hz),7.28(1H, dd, J=5.0 and 7.1 Hz), 7.45(1H, d, J=8.3 Hz), 7.74-7.79(2H, m),7.95(1H, s), 8.48(1H, d, J=8.5 Hz).

EXAMPLE 297 Synthesis of1-(butanesulfonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)benzimidazole(361)

In the same manner as in Example 98, 0.142 g of1-(butanesulfonylcarbamoyl)-2-methyl-1-(2-pyridylmethyl)benzimidazole(361) were formed from 0.500 g of6-carboxy-2-methyl-1-(2-pyridylmethyl)benzimidazole, 0.394 g ofN,N'-carbonyldiimidazole, 0.334 g of 1-butanesulfonamide and 0.370 g ofdiazabicycloundecene.

Properties of Compound (361):

¹ H-NMR(DMSO-d6, δ): 0.83(3H, t, J=7.3 Hz), 1.28-1.36(2H, m),1.52-1.58(2H, m), 2.55(3H, s), 3.06(2H, t, J=7.9 Hz), 5.56(2H, s),7.17(1H, d, J=7.8 Hz), 7.29(1H, dd, J=4.2 and 7.3 Hz), 7.43(1H, d, J=8.4Hz), 7.77(1H, dt, J=1.8 and 7.7 Hz), 7.81(1H, dd, J=1.4 and 8.4 Hz),7.96(1H, s), 8.50(1H, d, J=4.7 Hz).

IR(Nujol): 1674 cm⁻¹.

mp: 139° C. (decomp.).

EXAMPLE 298 Synthesis of6-ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)benzimidazole (362)

In the same manner as in Example 263, 0.51 g of6-ethoxycarbonyl-2-methyl-1-(4-nitrobenzyl)benzimidazole (362) wereformed from 0.67 g of ethyl 4-acetylamino-3-aminobenzoate, 0.39 g ofsodium carbonate, 0.14 g of sodium iodide and 0.78 g of 4-nitrodibenzylbromide.

Properties of Compound (362):

¹ H-NMR(CDCl₃, δ): 1.39(3H, t, J=7.1 Hz), 2.59(3H, s), 4.38(2H, q, J=7.1Hz), 5.49(2H, s), 7.20(2H, d, J=8.6 Hz), 7.76(1H, d, J=8.5 Hz), 7.94(1H,d, J=1.1 Hz), 8.01(1H, dd, J=1.4 and 8.5 Hz), 8.20(2H, d, J=8.6 Hz).

EXAMPLE 299 Synthesis of1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (363)

Six milliliters of ethanol and 0.8 ml of acetic acid were added to 0.50g of 1-(4-nitrobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 0.47 gof reduced iron, and the mixture was refluxed for 4.5 hours. Thereaction mixture was extracted with water and with ethyl acetate. Theorganic layer was washed with water, dried, and then concentrated underreduced pressure to give 0.46 g of1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole (363).

Properties of Compound (363):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.2 Hz), 2.59(3H, s), 4.38(2H, q, J=7.2Hz), 5.25(2H, s), 6.61(2H, d, J=8.6 Hz), 6.87(2H, d, J=8.6 Hz), 7.71(1H,d, J=8.3 Hz), 7.96(1H, dd, J=1.5 and 8.4 Hz), 8.05(1H, d, J=1.3 Hz).

EXAMPLE 300 Synthesis of1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole (364)

A solution of 0.25 g of benzoyl chloride in 4 ml of chloroform was addedto a solution of 0.45 g of1-(4-aminobenzyl)-6-ethoxycarbonyl-2-methylbenzimidazole and 0.15 g ofpyridine in 8 ml of chloroform, and the mixture was stirred at roomtemperature for 16 hours. The reaction mixture was extracted with waterand then with chloroform. The organic layer was concentrated underreduced pressure to give 0.33 g of1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole (364).

Properties of Compound (364)

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.1 Hz), 2.59(3H, s), 4.38(2H, q, J=7.1Hz), 5.37(2H, s), 7.06(2H, d, J=8.5 Hz), 7.46-7.50(2H, m), 7.53-7.57(1H,m), 7.61(2H, d, J=8.5 Hz), 7.72(1H, d, J=8.4 Hz), 7.84-7.86(2H, m),7.89(1H, br s), 7.98(1H, dd, J=1.5 and 8.5 Hz), 8.03(1H, s).

EXAMPLE 301 Synthesis of1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole (365)

In the same manner as in Example 53, 0.28 g of1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole (365) wereformed from 0.31 g of1-[(4-benzoylamino)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of the compound (365):

¹ H-NMR(DMSO-d6, δ): 2.58(3H, s), 5.52(2H, s), 7.12(2H, d, J=8.5 Hz),7.48-7.52(2H, m), 7.54-7.58(1H, m), 7.61(1H, d, J=8.4 Hz), 7.73(2H, d,J=8.6 Hz), 7.79(1H, dd, J=1.5 and 8.4 Hz), 7.90-7.92(2H, m), 8.07(1H, d,J=1.2 Hz), 10.26(1H, s), 12.73(1H, br s).

EXAMPLE 302 Synthesis of1-[(4-benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(366)

In the same manner as in Example 98, 0.14 g of1-[(4-benzoylamino)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(366) were obtained from 0.26 g of1-[(4-benzoylamino)benzyl]-6-carboxy-2-methylbenzimidazole, 0.17 g ofN,N'-carbonyldiimidazole, 0.14 g of 1-butanesulfonamide and 0.16 g ofdiazabicycloundecene.

Properties of Compound (366):

¹ H-NMR(DMSO-d6, δ): 0.85(3H, t, J=7.4 Hz), 1.40(2H, m), 1.68(2H, m),2.56(3H, s), 3.52(2H, t, J=7.8 Hz), 5.50(2H, s), 7.15(2H, d, J=8.6 Hz),7.50(2H, t, J=7.5 Hz), 7.55-7.59(1H, m), 7.64(1H, d, J=8.5 Hz), 7.74(2H,d, J=8.6 Hz), 7.79(1H, dd, J=1.6 and 8.5 Hz), 7.90-7.92(2H, m), 8.24(1H,d, J=1.3 Hz), 10.27(1H, s), 11.92(1H, br s).

IR(Nujol): 1693 cm⁻¹.

mp: 267.5-268.1° C.

EXAMPLE 303 Synthesis of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole(367)

In the same manner as in Example 263, 0.320 g of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole(367) were formed from 0.405 g of ethyl 4-acetylamino-3-aminobenzoate,0.253 g of potassium carbonate, 0.082 g of sodium iodide and 0.500 g of4-chloromethylstilbene.

Properties of Compound (367):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.2 HJz), 2.6(3H, s), 4.38(2H, q, J=7.1Hz), 5.38(2H, s), 7.01-7.09(4H, m), 7.26(1H, t, J=7.4 Hz), 7.35(2H, t,J=7.5 Hz), 7.45(2H, d, J=8.2 Hz), 7.49(2H, d, J=7.5 Hz), 7.73(1H, d,J=8.5 Hz), 7.99(1H, dd, J=1.5 and 8.4 Hz), 8.30(1H, d, J=1.2 Hz).

EXAMPLE 304 Synthesis of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole(368)

Five-percent palladium on carbon was added to a solution of 0.320 g of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole in10 ml of ethanol in a nitrogen atmosphere, and the mixture was stirredin a hydrogen atmosphere for 23 hours. The solid material was separatedthrough filtration, and the filtrate was concentrated to give6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole(368). This compound was used in the subsequent reaction at once.

EXAMPLE 305 Synthesis of6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]benzimidazole (369)

In the same manner as in Example 53, 0.242 g of6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole (369) wereformed from 0.283 g of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole.

Properties of Compound (369)

¹ H-NMR(DMSO-d6, δ): 2.56(3H, s), 2.82(4H, s), 5.51(2H, s), 7.02(2H, d,J=8.1 Hz), 7.11-7.27(7H, m), 7.61(1H, d, J=8.4 Hz), 7.78(1H, dd, J=1.5and 8.04(1H, s), 12.72(1H, s).

EXAMPLE 306 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethyl)benzyl]benzimidazole(370)

In the same manner as in Example 98, 0.249 g of6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethyl)benzyl]benzimidazole(370) were formed from 0.225 g of6-carboxy-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole, 1.214 g ofN,N'-carbonyldiimidazole, 0.167 g of 1-butanesulfonamide and 0.185 g ofdiazabicycloundecene.

Properties of Compound (370):

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.4 Hz), 1.35-1.42(2H, m),1.63-1.71(2H, m), 2.53(3H, s), 2.83(4H, s), 3.52(2H, t, J=7.7 Hz),5.49(2H, s), 7.04(2H, d, J=8.0 Hz), 7.12-7.25(7H, m), 7.64(1H, d, J=8.4Hz), 7.79(1H, dd, J=1.7 and 8.5 Hz), 8.22(1H, d, J=1.3 Hz), 11.92(1H,s).

IR(Nujol): 1682 cm⁻¹.

mp: 95.4-99.0° C.

PRODUCTION EXAMPLE 60 Production of 4-benzoylbenzyl bromide

In the same manner as in Production Example 48, 5.28 g of4-benzoylbenzyl bromide were formed from 3.92 g of 4-methylbenzophenone,4.28 g of N-bromosuccinimide and 0.40 g of 2,2'-azobisisobutylonitrile.

Properties of the compound:

¹ H-NMR(CDCl₃, δ): 4.54(2H, s), 7.47-7.52(4H, m), 7.58-7.62(1H, m),7.77-7.82(4H, m).

EXAMPLE 307 Synthesis of1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole (371)

In the same manner as in Example 263, 0.70 g of1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl-2-methylbenzimidazole (371) wereformed from 0.56 g of ethyl 4-acetylamino-3-aminobenzoate, 0.33 g ofsodium carbonate, 0.11 g of sodium iodide and 0.83 g of 4-benzoylbenzylbromide.

Properties of Compound (371):

¹ H-NMR(CDCl₃, δ): 1.40(3H, t, J=7.2 Hz), 2.61(3H, s), 4.39(2H, q, J=7.2Hz), 5.47(2H, s), 7.14(2H, d, J=8.2 Hz), 7.45-7.48(2H, m), 7.56-7.60(1H,m), 7.74-7.77(5H, m), 7.99-8.02(2H, m).

EXAMPLE 308 Synthesis of1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole (372)

In the same manner as in Example 53, 0.55 g of1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole (372) were formedfrom 0.68 g of1-[(4-benzoyl)benzyl]-6-ethoxycarbonyl]-2-methylbenzimidazole.

Properties of Compound (372):

¹ H-NMR(DMSO-d6, δ): 2.57(3H, s), 5.71(2H, s), 7.25(2H, d, J=8.2 Hz),7.52(2H, t, J=7.7 Hz), 7.62-7.66(2H, m), 7.68-7.72(4H, m), 7.80(1H, dd,J=1.3 and 8.4 Hz), 8.08(1H, d, J=1.1 Hz), 12.72(1H, br s).

EXAMPLE 309 Synthesis of1-[(4-benzoyl)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(373)

In the same manner as in Example 98, 0.13 g of1-[(4-benzoyl)benzyl]-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(373) were formed from 0.52 g of1-[(4-benzoyl)benzyl]-6-carboxy-2-methylbenzimidazole, 0.34 g ofN,N'-carbonyldiimidazole, 0.29 g of 1-butanesulfonamide and 0.32 g ofdiazabicycloundecene.

Properties of Compound (373):

¹ H-NMR(DMSO-d6, δ): 0.84(3H, t, J=7.4 Hz), 1.38(2H, m), 1.66(2H, m),2.54(3H, s), 3.48(2H, t, J=7.7 Hz), 5.67(2H, s), 7.27(2H, d, J=8.2 Hz),7.51-7.55(2H, m), 7.63-7.73(6H, m), 7.81(1H, dd, J=1.6 and 8.5 Hz),8.21(1H, d, J=1.4 Hz).

IR(Nujol): 1660 cm⁻¹.

mp: 111.0-112.4° C.

Mass(FAB): m/e 490(M+1).

EXAMPLE 310 Synthesis of6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole (374)

In the same manner as in Example 53, 0.237 g of6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole (374) wereformed from 0.500 g of6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole.

Properties of Compound (374):

¹ H-NMR(DMSO-d6, δ): 2.59(3H, s), 5.58(2H, s), 7.12(2H, d, J=8.2 Hz),7.21(2H, s), 7.26(1H, t, J=7.4 Hz), 7.36(2H, t, J=7.6 Hz), 7.57(4H, d,J=8.0 Hz), 7.62(1H, d, J=8.4 Hz), 7.79(1H, dd, J=1.5 and 8.4 Hz),8.07(1H, d, J=1.2 Hz), 12.73(1H, s).

EXAMPLE 311 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole(375)

In the same manner as in Example 98, 0.239 g of6-(1-butanesulfonylcarbamoyl)-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole(375) were formed from 0.237 g of6-carboxy-2-methyl-[4-(2-phenylethenyl)benzyl]benzimidazole, 0.209 g ofN,N'-carbonyldiimidazole, 0.176 g of 1-butanesulfonamide and 0.195 g ofdiazabicycloundecene.

Properties of Compound (375):

¹ H-NMR(DMSO-d6, δ): 0.86(3H, t, J=7.4 Hz), 1.35-1.43(2H, m),1.63-1.70(2H, m), 2.56(3H, s), 3.52(2H, t, J=7.6 Hz), 5.55(2H, s),7.15(2H, d, J=8.2 Hz), 7.22(2H, s), 7.26(1H, t, J=7.4 Hz), 7.36(2H, t,J=7.6 Hz), 7.57(1H, d, J=7.3 Hz), 7.58(1H, d, J=8.2 Hz), 7.66(1H, d,J=8.5 Hz), 7.80(1H, d, J=8.4 Hz), 8.24(1H, s), 11.93(1H, brs).

IR(Nujol): 1680 cm⁻¹.

mp: 140.3-143.4° C.

EXAMPLE 312 Synthesis of1-(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (376)

In the same manner as in Example 263, 0.47 g of1-(dibenzofuran-2-ylmethyl)-6-ethoxycarbonyl-2-methylbenzimidazole (376)were formed from 0.480 g of ethyl 4-acetylamino-3-aminobenzoate, 0.274 gof sodium carbonate, 0.097 g of sodium iodide and 0.56 g of2-bromomethyldibenzofuran.

Properties of Compound (376):

¹ H-NMR(CDCl₃, δ): 1.38(3H, t, J=7.1 Hz), 2.62(3H, s), 4.36(2H, q, J=7.1Hz), 5.54(2H, s), 7.19(1H, dd, J=1.6 and 8.5 Hz), 7.32(1H, t, J=7.6 Hz),7.43-7.59(4H, m), 7.76(1H, d, J=8.4 Hz), 7.85(1H, d, J=7.1 Hz), 8.00(1H,dd, J=1.3 and 8.4 Hz), 8.07(1H, d, J=1.2 Hz).

EXAMPLE 313 Synthesis of6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole (377)

In the same manner as in Example 53, 0.336 g of6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole (377) wereformed from 0.46 g of 6-ethoxycarbonyl-2-methylbenzimidazole.

Properties of Compound (377):

¹ H-NMR(DMSO-d6, δ): 2.63(3H, s), 5.71(2H, s), 7.27(1H, d, J=8.5 Hz),7.36(1H, t, J=7.5 Hz), 7.50(1H, t), 7.61-7.68(3H, m), 7.78(1H, d, J=8.3Hz), 7.97(1H, s), 7.07-8.11(2H, m).

EXAMPLE 314 Synthesis of1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(378)

In the same manner as in Example 98, 0.249 g of1-(dibenzofuran-2-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(378) were formed from 0.255 g of6-carboxy-1-(dibenzofuran-2-ylmethyl)-2-methylbenzimidazole, 0.197 g ofN,N'-carbonyldiimidazole, 0.167 g of 1-butanesulfonamide and 0.185 g ofdiazabicycloundecene.

Properties of Compound (378):

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.4 Hz), 1.36(2H, m), 1.65(2H, m),2.60(3H, s), 3.50(2H, t, J=7.7 Hz), 5.69(2H, s), 7.29(1H, dd, J=1.96 and8.7 Hz), 7.34-7.38(1H, m), 7.48-7.52(1H, m), 7.63-7.68(3H, m), 7.81(1H,dd, J=1.7 and 8.5 Hz), 8.00(1H, d, J=1.4 Hz), 8.94(1H, d, J=7.1 Hz),8.28(1H, d, J=1.4 Hz), 12.70(1H, br s).

IR(Nujol): 1682 cm⁻¹.

mp: 224.1-229.8° C.

PRODUCTION EXAMPLE 61 Production ofN-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide

In the same manner as in Production Example 28, 6.30 g ofN-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide were obtained from5.15 g of 3-acetylamino-4-nitrobenzoic acid, 5.59 g ofN,N'-carbonyldiimidazole, 4.73 g of 1-butanesulfonamide and 5.25 g ofdiazabicycloundecene.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.4 Hz), 1.40(2H, m), 1.68(2H, m),2.07(3H, s), 3.51(2H, t), 7.83(1H, dd, J=1.8 and 8.5 Hz), 8.03(1H, d,J=8.5 Hz), 8.07(1H, d, J=1.8 Hz), 10.43(1H, s), 12.64(1H, br s).

PRODUCTION EXAMPLE 62 Production ofN-1-butanesulfonyl-3-amino-4-nitrobenzamide

A mixture containing 6.30 g ofN-1-butanesulfonyl-3-acetylamino-4-nitrobenzamide, a 10% sodiumhydroxide aqueous solution, 300 ml of ethanol and 200 ml of water wasstirred at room temperature for 4 hours and then at 50° C. for 3 hours.The solvent was distilled off to approximately a half volume, and theresidue was adjusted to a pH of 2 with 10% hydrochloric acid. Thecrystals precipitated were collected, and were dried under reducedpressure to give 5.22 g of N-1-butanesulfonyl-3-amino-4-nitrobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.87(3H, t, J=7.4 Hz), 1.40(2H, m), 1.66(2H, m),3.49(2H, m), 6.99(1H, dd, J=1.8 and 9.0 Hz), 7.49(1H, d, J=1.8 Hz),7.55(2H, br s), 8.04(1H, d, J=9.0 Hz), 12.28(1H, br s).

PRODUCTION EXAMPLE 63 Production ofN-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide

A solution containing 1.10 g ofN-1-butanesulfonyl-3-amino-4-nitrobenzamide, 0.273 g of sodium iodide,1.54 g of potassium carbonate, 2.17 g of 2,4-dichlorobenzyl chloride and10 ml of methanol was stirred at 60° C. for 24 hours. Further, 2.00 g of2,4-dichlorobenzyl chloride were added thereto, and the mixture washeated at 60° C. for 36 hours. To the reaction solution were added ethylacetate and a saturated aqueous solution of sodium hydrogencarbonate,and N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide wasextracted in the aqueous layer. The organic layer was concentrated togive 0.885 g ofN-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.3 Hz), 1.29(2H, m), 1.49(2H, m),2.97(2H, m), 4.66(2H, d, J=6.0 Hz), 7.22(1H, d, J=8.9 Hz), 7.27(1H, s),7.31(1H, d, J=8.4 Hz), 7.37(1H, d, J=8.3 Hz), 7.65(1H, s), 8.04(1H, d,J=8.9 Hz), 8.57(1H, t).

PRODUCTION EXAMPLE 64 Production ofN-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide

N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide (0.505g) was added to a mixture of 1.32 g of sodium hydrosulfite, 1 ml ofethanol, 1 ml of tetrahydrofuran and 1 ml of water at room temperature.The mixture was heat-refluxed for 40 minutes. The solvent was distilledoff under reduced pressure, and water was added to the residue. Thesolid material precipitated was collected, and was dried. Further, theresulting material was washed with a mixed solution of 10 ml of methanoland 3 ml of water, and was dried to give 0.220 g ofN-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide.

Properties of the compound:

¹ H-NMR(DMSO-d6, δ): 0.93(3H, t, J=7.4 Hz), 1.45(2H, m), 1.83(2H, m),3.57(2H, m), 5.45(2H, s), 6.36(1H, d, J=8.2 Hz), 7.11(1H, d, J=8.3 Hz),7.51(1H, s), 7.75(1H, d), 7.79(1H, d), 7.88(1H, s).

EXAMPLE 315 Synthesis of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole(379)

A mixture of 0.220 mg ofN-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide, 0.3 mlof tetramethoxymethane and 2.0 ml of acetic acid was stirred at 60° C.for 4 hours. Acetic acid was distilled off under reduced pressure, andthe residue was extracted with chloroform and with water. The chloroformlayer was concentrated, and 4.0 ml of methanol and 36% hydrochloric acid(4 drops). were added to the residue. The mixture was stirred at 60° C.for 2 hours. The reaction solution was neutralized with a saturatedaqueous solution of sodium hydrogencarbonate. The crystals precipitatedwere washed with water, and were dried to give 0.207 g of6-(1-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-hydroxybenzimidazole(379).

Properties of Compound (379):

¹ H-NMR(DMSO-d6, δ): 0.83(3H, t, J=7.3 Hz), 1.36(2H, m), 1.61(2H, m),3.40(2H, m), 5.08(2H, s), 6.94(1H, d, J=8.3 Hz), 7.11(1H, d, J=8.2 Hz),7.36(1H, dd, J=2.0 and 8.4 Hz), 7.58(1H, s), 7.68-7.73(2H, m), 11.47(1H,br s), 11.77(1H, br s).

IR(Nujol): 1689 cm⁻¹.

mp: 254-256° C.

Mass(FD): m/e 455(M).

EXAMPLE 316 Synthesis of6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole (380)

In accordance with Example 263, 0.87 g of6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole (380) wereformed from 2.22 g of ethyl 4-acetylamino-3-aminobenzoate, 1.27 g ofsodium carbonate, 0.45 g of sodium iodide and 2.28 g of2-bromomethylquinoline.

Properties of the compound (380):

¹ H-NMR(DMSO-d6, δ): 1.27(3H, t, J=7.1 Hz), 2.62(3H, s), 4.26(2H, q,J=7.1 Hz), 5.85(2H, s), 7.35(1H, d, J=8.5 Hz), 7.58(1H, m), 7.63(1H, d,J=8.4 Hz), 7.73(1H, m), 7.78(1H, dd, J=1.3 and 8.4 Hz), 7.86(1H, d,J=8.4 Hz), 7.95(1H, d, J=8.0 Hz), 8.14(1H, s), 8.36(1H, d, J=8.5 Hz).

EXAMPLE 317 Synthesis of6-carboxy-2-methyl-(2-quinolylmethyl)benzimidazole (381)

In the same manner as in Example 53, 0.46 g of6-carboxy-2-methyl-(2-quinolylmethyl)benzimidazole (381) were formedfrom 0.85 g of6-ethoxycarbonyl-2-methyl-1-(2-quinolylmethyl)benzimidazole.

Properties of Compound (381):

¹ H-NMR(DMSO-d6, δ): 2.62(3H, s), 5.83(2H, s), 7.35(1H, d, J=8.5 Hz),7.57(1H, m), 7.60(1H, d, J=8.5 Hz), 7.72(1H, t, J=7.6 Hz), 7.77(1H, d,J=8.4 Hz), 7.86(1H, d, J=8.4 Hz), 7.94(1H, d, J=8.1 Hz), 8.11(1H, s),8.35(1H, d, J=8.5 Hz).

EXAMPLE 318 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole(382)

In the same manner as in Example 98, 0.088 g of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-(2-quinolylmethyl)benzimidazole(382) were formed from 0.222 g of6-carboxy-2-methyl-1-(2-quinolylmethyl)benzimidazole, 0.195 g ofN,N'-carbonyldiimidazole, 0.165 g of 1-butanesulfonamide and 0.183 g ofdiazabicycloundecene.

Properties of Compound (382):

¹ H-NMR(DMSO-d6, δ): 0.82(3H, t, J=7.3 Hz), 1.36(2H, m), 1.64(2H, m),2.61(3H, s), 3.48(2H, t, J=7.4 Hz), 5.82(2H,s), 7.32(1H,d, J=8.5 Hz),7.58(1H, m), 7.65(1H, d, J=8.5 Hz), 7.73(1H, t, J=7.6 Hz), 7.78(1H, m),7.87(1H, d, J=8.5 Hz), 7.95(1H,d, J=8.1 Hz), 8.23(1H, s), 8.37(1H, d,J=8.5 Hz), 11.86(1H,brs).

IR(Nujol): 1684 cm⁻¹.

mp: 185.5-187.5° C.

PRODUCTION EXAMPLE 65 Production of ethyl4-amino-3-(2,4-dichlorobenzylamino)benzoate

Crude ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate was formed from1.40 g of 3-(2,4-dichlorobenzylamino)-4-nitrobenzoate and 4.50 g ofsodium hydrosulfite in the same manner as in Production Example 64. Thiscompound was used in the subsequent reaction at once.

EXAMPLE 319 Synthesis of1-(2,4-dichlorobenzylamino)-2-hydroxy-6-ethoxycarbonylbenzimidazole(383)

In the same manner as in Example 315, 0.400 g of1-(2,4-dichlorobenzylamino)-2-hydroxy-6-ethoxycarbonylbenzimidazole(383) were formed from ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoateobtained in the above-mentioned Production Example 63 and 2.60 g oftetramethoxymethane.

Properties of Compound (383):

¹ H-NMR(DMSO-d6, δ): 1.27(3H, t, J=7.1 Hz), 4.24(2H, q, J=7.1 Hz),5.12(2H, s), 7.04(1H, d, J=8.4 Hz), 7.12(1H, d, J=8.2 Hz), 7.37(1H, dd,J=2.1 and 8.4 Hz), 7.51(1H, s), 7.67-7.72(2H, m), 11.37(1H, br s).

EXAMPLE 320 Synthesis of6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole(384)

In the same manner as in Example 263, 0.30 g of6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole(384) were formed from 0.87 g of ethyl 4-acetylamino-3-aminobenzoate,0.53 g of sodium carbonate, 0.18 g of sodium iodide and 0.87 g of4-bromo-3-bromomethylisoquinoline.

Properties of Compound (384):

¹ H-NMR(DMSO-d6, δ): 1.26(3H, t, J=7.0 Hz), 2.59(3H, s), 4.24(2H, q,J=7.0 Hz), 5.93(2H, s), 7.61(1H, d, J=8.4 Hz), 7.75-7.80(2H, m).7.99(1H, m), 8.03(1H, s), 8.13(1H, d, J=8.1 Hz), 8.23(1H, d, J=8.5 Hz),9.12(1H, s).

EXAMPLE 321 Synthesis of6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)methyl]benzimidazole (385)

In the same manner as in Example 53, 0.118 g of6-carboxy-2-methyl-[3-(4-bromoisoquinolyl)methyl]benzimidazole (385)were formed from 0.290 g of6-ethoxycarbonyl-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole.This compound was used in the subsequent reaction at once.

EXAMPLE 322 Synthesis of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole(386)

In the same manner as in Example 98, 0.075 g of6-(1-butanesulfonylcarbamoyl)-2-methyl-1-[3-(4-bromoisoquinolyl)methyl]benzimidazole(386) were formed from 0.111 g of6-carboxy-2-methyl-1-[3-(4-bromoisoquinolyl)-methyl]benzimidazole, 0.097g of N,N'-carbonyldiimidazole, 0.082 g of 1-butanesulfonamide and 0.091g of diazabicycloundecene.

Properties of Compound (386):

¹ H-NMR(DMSO-d6, δ): 0.81(3H, t, J=7.4 Hz), 1.35(2H, m), 1.62(2H, m),2.54(3H, s), 3.46(2H, t, J=7.5 Hz), 5.91(2H, s), 7.63(1H, d, J=8.5 Hz),7.76(1H, dd, J=8.5 and 1.4 Hz), 7.79(1H, t, J=7.6 Hz), 8.00(1H, t, J=7.9Hz), 8.08(1H, t, J=l.1Hz), 8.13(1H, d, J=8.2 Hz), 8.24(1H, d, J=8.5 Hz),9.11(1H,s), 11.81(1H, brs).

IR(Nujol): 1678 cm⁻¹.

mp: 258-259° C.

Mass(FAB): m/e 515, 517(M+1).

From among the compounds of the present invention, the typical compoundswere selected, and were tested for pharmacological properties.

TEST EXAMPLE 1

Stimulatory activity of triglyceride (TG) accumulation in 3T3-L1 cells(pre-adipocytes).

Test Compound

6-benzylsulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole

Devices Used

1. Centrifuge: TOMY LC-122

2. Incubator: ESPEC BNA-121D

3. Mixer: Automatic Labo-Mixer

4. Water bath: TAITEC PERSONAL-11

5. Spectrophotometer: Shimadzu UV Visible Spectro-photometer UV-160A

6. 24-well plate: IWAKI GLASS CORNING

Reagents Used

1. Medium: Dulbecco minimum essential medium (MEM)+5% fetal calf serum(FCS)

2. PBS (-): solution having the following composition

    ______________________________________                                               NaCl         0.8    g/liter                                              KCl 0.2                                                                       Na.sub.2 HPO.sub.4 1.15                                                       KH.sub.2 PO.sub.4 0.2                                                       ______________________________________                                    

3. Solution of EDTA and trypsin: 0.02% EDTA+0.25% trypsin/PBS(-)

4. Dexamethasone: made by Sigma

5. IBMX (3-isobutyl-1-methylxanthine): made by Sigma

6. Insulin: made by Sigma

7. DMSO (dimethylsulfoxide): made by Wako Pure Chemical Industries, Ltd.

8. TG measuring kit: Triglyceride-Test Wako (acetyl-acetone method):made by Wako Pure Chemical Industries, Ltd.

9. 0.1-N NaOH solution: prepared by diluting a iN NaOH solution to 10times with distilled water.

10. Bio-Rad Protein Assay Reagent: made by Bio-Rad.

11. Bovine albumin: made by Sigma

Test Method

Preparation of 3T3-L1 Cells

3T3-L1 cells just before a confluent state were prepared in an F75flask. The medium was removed, and the residue was washed twice with 5ml of PBS (-). The cells were detached using a solution of EDTA andtrypsin. Ten milliliters of the medium were added thereto to form asuspension. This suspension was collected in a 50-milliliter centrifugetube, and was subjected to centrifugation at 1,000 rpm for 5 minutes.Thus, the cells were precipitated, and the supernatant was removed. Thecells were re-suspended in 20 ml of the medium, and the number of cellswas counted. The suspension was adjusted such that the concentration ofthe cells reached 6×10⁴ cells/ml, and was inoculated into a 24-wellplate in an amount of 1 ml/well. In this state, the incubation wasconducted in an incubator at 37° C. in 5% CO₂ for 2 days.

Preparation and Addition of Dexamethasone and IBMX

A solution of 1-mM dexamethasone and 500-mM IBMX was prepared in DMSO.Further, this solution was diluted to 1,000 times with the medium toform a solution of 1 μM dexamethasone and 0.5 mM IBMX. At the same time,DMSO was diluted with the medium to form a 0.1% DMSO solution as well.

Subsequently, the 24-well plate containing the incubated 3T3-L1 cellswas withdrawn from the incubator. It was identified using a microscopethat the cells became confluent, and the medium was removed throughsuction. The 2 wells of the 24-well plate were charged with the 0.1%DMSO solution in an amount of 1 ml/well, and the remaining 22 wells werecharged with the solution of 1-μM dexamethasone and 0.5 mM IBMX in anamount of 1 ml/well. In this state, the incubation was conducted in anincubator at 37° C. in 5% CO₂ for 1 day.

Preparation and Addition of a Test Chemical Agent and Insulin

A test chemical agent was diluted with DMSO to 1×10⁻² M, 1×10⁻³ M and1×10⁻⁴ M. The dilute solutions were further diluted to 500 times, andwere adjusted to 2×10⁻⁵ M, 2×10⁻⁶ M and 2×10⁻⁷ M respectively. At thesame time, a 0.2% DMSO solution was also prepared. Insulin which hadbeen adjusted to 100 μM (in 0.2% bovine serum albumin (BSA) and 3-mMHCl) and had been stored at -80° C. was naturally thawed, diluted to50,000 times with the medium, and adjusted to 2-nM.

Subsequently, the 24-well plate to which dexamethasone and IBMX had beenadded the preceding day was withdrawn from the incubator. It wasidentified using a microscope that the shape of the cells was changedwith the addition of dexamethasone and IBMX. Then, the medium wasremoved through suction. The 2 wells to which the 0.1% DMSO solution hadbeen added the preceding day were charged with the 0.2% DMSO solution inan amount of 500 μl/well and the medium (this was required to check thecell state at that time). The remaining 22 wells (containing thesolution of dexamethasone and IBMX) were charged with the 0.2% DMSOsolution (2 wells). or the test chemical agent (20 wells). in an amountof 500 μl/well and then with the insulin solution in an amount of 500μl/well. In this state, the incubation was conducted in an incubator at37° C. in 5% CO₂ for from 4 to 5 days.

Measurement of Triglyceride (TG) and Protein

Four to five days after the addition of the test chemical agent and theinsulin solution, the 24-well plate was withdrawn from the incubator.The medium was discarded by decantation, and the remaining medium wasthen absorbed in a paper towel to completely remove the medium.Subsequently, the residue was extracted twice with isopropyl alcohol,and TG was measured at a wavelength of 410 nm using a TG-measuring kit(acetyl-acetone method). Subsequently, isopropyl alcohol was completelyvaporized from the plate in which the extraction with isopropyl alcoholwas completed. This plate was then charged with a 0.1-N NaOH solution inan amount of 400 μl/well, and was allowed to stand at room temperaturefor 30 minutes to dissolve the cells. This solution was sampled into atube in an amount of 50 μl. Further, a solution obtained by diluting aBio-Rad protein assay reagent to 5 times with distilled water was addedto the tube in an amount of 2.5 ml. The mixture was stirred well, andprotein was measured at a measurement wavelength of 595 nm using aspectrophotometer.

Results

The stimulatory activity of the test compound for TG accumulation wascalculated, when 1×10⁻⁶ M of a control compound, pioglitazone, wasdefined as 100% and insulin (+) without the chemical agent was definedas 0%. The result is shown following.

                  TABLE 1                                                         ______________________________________                                        Concentration Stimulatory activity of                                           (M) TG accumulation (%)                                                     ______________________________________                                          1 × 10.sup.-5 38.2%                                                   ______________________________________                                    

TEST EXAMPLE 2

Test for activity of decreasing plasma glucose using db/db mice

Test Compounds

6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole(177)

6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole(163)

1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole(172)

Animal Used

Five-week-old female mice [C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm +m/+m(Jackson Laboratory) were purchased, and were kept for 2 to 3 weeks.Then, these mice were used in the test.

Preparation of an Agent

A test compound was mixed with a powdered chow (CE-2, made by NipponClea) using a mortar. According to the amount of food intake of themouse, the mixing ratios, 0.1%, 0.03%, and 0.01% corresponded to 100,30, and 10 mg/kg body weight, respectively. The mixed chow was changedtwice a week. The feed amount and the remaining amount were recorded,and the intake was calculated from the difference therebetween.

Test Schedule

The female db/db mice were grouped according to the body weight, theplasma glucose and the plasma triglyceride concentrations. Then, themixture containing the test compound was administered to the mice for 14days (from 8 to 10 weeks old). In the morning on day 7 and day 14, theblood was collected from the orbital venous plexus using heparinizedglass capillary tubes (Chase Heparinized Capillary Tubes), and a plasmafraction was obtained through centrifugal separation. Plasma glucose,triglyceride, and insulin concentrations were measured on day 0 and day14 as well as plasma glucose and triglyceride concentrations on day 7.The body weight was measured on day 0, day 7, and day 14. After thefinal collection of the blood, the mice were killed using CO₂ gas.

Measurement Method

The plasma glucose was measured by a glucose oxidase method (GlucoseCII-Test Wako made by Wako Pure Chemical Industries, Ltd.) using from 10to 15 μl of plasma. The plasma triglyceride concentration was measuredby a GPO-p-chlorophenol method (Triglyceride G-Test Wako made by WakoPure Chemical Industries, Ltd.) or a GPO-DAOS method (TriglycerideE-Test Wako) using from 10 to 15 μl of plasma. The above-mentionedmeasurements were conducted immediately after the blood collection. Theplasma insulin concentration was measured by radio immuno assay method(Phadesef Insulin RIA Kit made by Cabi Pharmacia) using 20 μl of plasma(which can be stored at -20° C.).

Results

The difference in the plasma glucose and the plasma triglycerideconcentrations between the db/db mouse and the +/+ mouse was defined as100%, and the rate (%) of decrease in the plasma glucose and the plasmatriglyceride concentrations of the group to which the test compound wasadministered was calculated. The results were shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound               Activity of decreasing                                   No. Dose (mg/kg) plasma glucose (%)                                         ______________________________________                                        (177)       30         34.5                                                     (163) 30 72                                                                   (172) 10 70-80                                                              ______________________________________                                    

INDUSTRIAL APPLICABILITY

Herein provided are novel benzimidazole derivatives and theirpharmaceutically acceptable salts. These compounds and their salts haveblood sugar level-depressing activity or PDE5-inhibiting activity, andare useful for preventing and treating impaired glucose tolerance,diabetes (type II diabetes), diabetic complications such as diabeticnephropathy, diabetic neuropathy and diabetic retinopathy, syndrome ofinsulin resistance (e.g., insulin receptor disorders, Rabson-Mendenhallsyndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome,Lawrence syndrome, Cushing syndrome, acromegaly, etc.), hyperlipidemia,atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiacfailure, etc.), hyperglycemia(e.g., abnormal-saccharometabolism such asfeeding disorders, etc.), or hypertension; or stenocardia, hypertension,pulmonary hypertension, congestive heart failure, glomerulopathy (e.g.,diabetic glomerulosclerosis, etc.), tubulointerstitial disorders (e.g.,renopathy induced by FK506, cyclosporin, etc.), renal failure,atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty),distal angiopathy, cerebral apoplexy, chronic reversible obstructions(e.g., bronchitis, asthma (chronic asthma, allergic asthma), etc.),allergic rhinitis, urticaria, glaucoma, diseases characterized byenteromotility disorders (e.g., hypersensitive enteropathy syndrome,etc.), impotence (e.g., organic impotence, psychic impotence, etc.), anddiabetic complications (e.g., diabetic gangrene, diabetic arthropathy,diabetic glomerulosclerosis, diabetic dermatopathy, diabetic neuropathy,diabetic cataract, diabetic retinopathy, etc.), nephritis, cancerouscachexia, or restenosis after PTCA.

We claim:
 1. A benzimidazole derivative of the following formula, or itspharmaceutically acceptable salt: ##STR37## wherein R₂₇ represents ahydrogen atom, an alkyl group having up to 7 carbon atoms, a halo-loweralkyl group, an arylsulfonyl group, an aryl-lower alkyl group, aquinolyl-lower alkyl group, an isoquinolyl-lower alkyl group, ahalo-quinolyl-lower alkyl group, or a halo-isoquinolyl-lower alkylgroup; the aromatic ring moiety in said aryl-lower alkyl group may besubstituted by one or two substituents selected from the groupconsisting of a halogen atom, a lower alkyl group, a halo-lower alkylgroup, a cyanoaryl group, an amino group, a lower alkoxy group, a nitrogroup, a cyano group, an aryl group, a haloaryl group, anarylsulfonyl-lower alkyl group, an arylsulfonylamino group, anaryl-lower alkyloxy group, an aryl-lower alkyl group, a quinolyl group,an isoquinolyl group, an aryloxy group, an arylcarbonyl group, anarylcarbonylamino group, and an aryl-lower alkyloxy group substituted byone or two halogen atoms;R₂₈ represents a hydrogen atom, an alkyl grouphaving up to 7 carbon atoms, a halo-lower alkyl group, a loweralkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, anaryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group,a lower alkylthio group, a hydroxyl group, a mercapto group, an aminogroup, or a carboxyl group; R₂₅ represents an alkyl group having up to 8carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-loweralkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-loweralkyl group, an aryl group, a quinolyl group, an isoquinolyl group, anaryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl groupmay be substituted by a halogen atom, a lower alkyl group, a halo-loweralkyl group, a lower alkoxy group, or a nitro group; R₂₆ represents ahydrogen atom or a lower alkyl group; provided that, when R₂₅ and R₂₆are both lower alkyl groups, they may be bonded together to form a ring;Y represents a carbonyl group or a lower alkylene group; A represents asingle bond, or a lower alkylene or alkenylene group; and R₂₉ representsa hydrogen atom or a lower alkyl group.
 2. The benzimidazole derivativeor its pharmaceutically acceptable salt of claim 1, wherein R₂₇represents an aryl-lower alkyl group whole aromatic ring moiety may besubstituted by one or two substituents selected from the groupconsisting of the group consisting of a halogen atom, a lower alkylgroup, a halo-lower alkyl group, a cyanoaryl group, an amino group, alower alkoxy group, a nitro group, a cyano group, an aryl group, ahaloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylaminogroup, an aryl-lower alkyloxy group, an aryl-lower alkyl group, aquinolyl group, an isoquinolyl group, an arylcarbonylamino group, and anaryl-lower alkyloxy group substituted by one or two halogen atoms;R₂₅represents an alkyl group having up to 8 carbon atoms, a halo-loweralkyl group, a tri-lower alkylsilyl-lower alkyl group, a loweralkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an arylgroup, a quinolyl group, an isoquinolyl group, an aryloxy group, anarylcarbonyl group, an aryl-lower alkyl group, or a hydroxy-lower alkylgroup; said aryl group may be substituted by a halogen atom, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitrogroup; Y represents a carbonyl group; and A represents a single bond. 3.The benzimidazole derivative or its pharmaceutically acceptable salt ofclaim 1, wherein R₂₇ represents an aryl-lower alkyl group whose aromaticring moiety may be substituted by one or two substituents selected fromthe group consisting of a halogen atom and an aryl group;R₂₈ representsan alkyl group having up to 7 carbon atoms or a lower cycloalkyl group;Y represents a carbonyl group; and A represents a single bond.
 4. Thebenzimidazole derivative or its pharmaceutically acceptable salt ofclaim 1, wherein said derivative is selected from the group consistingof 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole,1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole,6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)benzimidazole,6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl-2-methylbenzimidazole,6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole,1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole,and1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole.5. A pharmaceutical composition comprising a compound of formula (IX) orits pharmaceutically acceptable salt: ##STR38## wherein R₂₇ represents ahydrogen atom, an alkyl group having up to 7 carbon atoms, a halo-loweralkyl group, an arylsulfonyl group, an aryl-lower alkyl group, aquinolyl-lower alkyl group, an isoquinolyl-lower alkyl group, ahalo-quinolyl-lower alkyl group, or a halo-isoquinolyl-lower alkylgroup; the aromatic ring moiety in said aryl-lower alkyl group may besubstituted by one or two substituents selected from the groupconsisting of a halogen atom, a lower alkyl group, a halo-lower alkylgroup, a cyanoaryl group, an amino group, a lower alkoxy group, a nitrogroup, a cyano group, an aryl group, a haloaryl group, anarylsulfonyl-lower alkyl group, an arylsulfonylamino group, anaryl-lower alkyloxy group, an aryl-lower alkyl group, a quinolyl group,an isoquinolyl group, an aryloxy group, an arylcarbonyl group, anarylcarbonylamino group, and an aryl-lower alkyloxy group substituted byone or two halogen atoms;R₂₈ represents a hydrogen atom, an alkyl grouphaving up to 7 carbon atoms, a halo-lower alkyl group, a loweralkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, anaryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group,a lower alkylthio group, a hydroxyl group, a mercapto group, an aminogroup, or a carboxyl group; R₂₅ represents an alkyl group having up to 8carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-loweralkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-loweralkyl group, an aryl group, a quinolyl group, an isoquinolyl group, anaryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl groupmay be substituted by a halogen atom, a lower alkyl group, a halo-loweralkyl group, a lower alkoxy group, or a nitro group; R₂₆ represents ahydrogen atom or a lower alkyl group; provided that, when R₂₅ and R₂₆are both lower alkyl groups, they may be bonded together to form a ring;Y represents a carbonyl group or a lower alkylene group; A represents asingle bond, or a lower alkylene or alkenylene group; and R₂₉ representsa hydrogen atom or a lower alkyl group, and a pharmaceuticallyacceptable excipient.
 6. A method for lowering the blood sugar of apatient and/or inhibiting PDE5 in a patient, which comprisesadministering to the patient an effective amount of a compound offormula (IX) or its pharmaceutically acceptable salt: ##STR39## whereinR₂₇ represents a hydrogen atom, an alkyl group having up to 7 carbonatoms, a halo-lower alkyl group, an arylsulfonyl group, an aryl-loweralkyl group, a quinolyl-lower alkyl group, an isoquinolyl-lower alkylgroup, a halo-quinolyl-lower alkyl group, or a halo-isoquinolyl-loweralkyl group; the aromatic ring moiety in said aryl-lower alkyl group maybe substituted by one or two substituents selected from the groupconsisting of a halogen atom, a lower alkyl group, a halo-lower alkylgroup, a cyanoaryl group, an amino group, a lower alkoxy group, a nitrogroup, a cyano group, an aryl group, a haloaryl group, anarylsulfonyl-lower alkyl group, an arylsulfonylamino group, anaryl-lower alkyloxy group, an aryl-lower alkyl group, a quinolyl group,an isoquinolyl group, an aryloxy group, an arylcarbonyl group, anarylcarbonylamino group, and an aryl-lower alkyloxy group substituted byone or two halogen atoms;R₂₈ represents a hydrogen atom, an alkyl grouphaving up to 7 carbon atoms, a halo-lower alkyl group, a loweralkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, anaryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group,a lower alkylthio group, a hydroxyl group, a mercapto group, an aminogroup, or a carboxyl group; R₂₅ represents an alkyl group having up to 8carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-loweralkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-loweralkyl group, an aryl group, a quinolyl group, an isoquinolyl group, anaryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl groupmay be substituted by a halogen atom, a lower alkyl group, a halo-loweralkyl group, a lower alkoxy group, or a nitro group; R₂₆ represents ahydrogen atom or a lower alkyl group; provided that, when R₂₅ and R₂₆are both lower alkyl groups, they may be bonded together to form a ring;Y represents a carbonyl group or a lower alkylene group; A represents asingle bond, or a lower alkylene or alkenylene group; and R₂₉ representsa hydrogen atom or a lower alkyl group.